ANTISENSE MODULATION OF EXPRESSION OF TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED FACTORS (TRAFs)

Abstract: Compositions and methods are provided for modulating the expression of tumor necrosis factor receptor-associated factor (TRAF). Antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding TRAF are preferred. Methods of using these compounds for modulation of TRAF expression and for treatment of diseases associated with expression of TRAF are provided.

Description: ANTISENSE MODULATION OF EXPRESSION OF TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED FACTORS (TRAFs) FIELD OF THE INVENTION The present invention provides compositions and methods for modulating the expression of tumor necrosis factor receptor-associated factors (TRAFs) . In particular, this invention relates to antisense compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding human TRAFs. Such oligonucleotides have been shown to modulate the expression of TRAFs. BACKGROUND OF THE INVENTION Tumor necrosis factor (TNF) receptor superfamily members regulate cellular proliferation, differentiation and apoptosis in inflammatory and immune responses . This receptor superfamily comprises a group of related cell- surface receptors including, but not limited to, types 1 and 2 TNF receptors (TNFR1 and TNFR2) , Fas, CD27, 4-IBB, CD40 and CD30. Signaling through TNF receptor superfamily members is initiated by oligomerization of the receptors with trimeric ligands, bringing intracellular domains in close proximity (Pullen et al . , Biochemistry 1998, 37, 11836-11845) . Two families of adaptor proteins that associate with TNF receptor superfamily members have been identified: the TNF receptor-associated factor (TRAF) family, and the death domain-containing protein family. Members of the TRAF family of proteins share an amino- terminal RING finger motif and a homologous carboxy- terminal region, referred to in the art as the TRAF domain (Yuan, J., Curr. Opin . Cell Biol . 1997, 9, 247-251. This conserved carboxy-terminal region binds to receptor cytoplasmic domains and mediates interactions with the signaling proteins NF-κB inducing kinase (NIK) and I- TRAFT/TANK (Cheng et al . , Science 1995, 267, 1494-1498; Cheng, G. and Baltimore, D., Genes Dev. 1996, 10, 963-973; Rothe et al . , Proc. Natl Acad. Sci . USA 1996, 93, 8241- 8246; Malinin et al . , Nature 1997, 385, 540-544). A predicted coiled-coil region mediating TRAF homo- and hetero-oligomerization is in a less conserved region N- terminal to the TRAF domain (Cao et al . , Nature 1996, 383, 443-446; Cheng et al . , Science 1995, 267, 1494-1498; Rothe " et al., Cell 1994, 78, 681-692; Sato et al . , FEBS Lett 1995, 358, 113-118; and Takeuchi et al . , J " . Biol . Chem 1996, 271, 19935-19942) . The mammalian TRAF family currently includes six members, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5 and TRAF-6. These proteins have generally been found within the cytosols of cells, either in association with cytosolic vesicles or at the plasma membrane after addition of selected TNF family cytokines to the cells. Members of the TRAF family mediate signals for various different receptors. Subsets of TRAF family members have been shown to interact with the TNF receptor family members (TNFR2, CD40, CD30, LTβR, ATAR, OX40 and 4-1BB) . For example, TRAF-1 and TRAF-2 were identified by their ability to interact with the cytoplasmic domains of TNFR2 (Rothe et al . , Cell 1994, 78, 681-691). TNFR2 has been associated with TNF's ability to stimulate cell proliferation and activation of NFKB (Tartaglia et al . , Proc . Natl Acad. Sci . USA 1991, 88, 9292-9296) . TRAF-1 is believed to be involved in the regulation of apoptosis (Speiser et al . , J " . Exp . Med. 1997, 185, 1777-1783). Depletion of TRAF-2 and its co-associated proteins has also been shown to increase the sensitivity of the cell to undergo apoptosis during activation of death inducing receptors such as TNFR1 (Duckett, C.S. and Thompson, C.B., Genes & Development 1997, 11, 2810-2821; Yeh et al., Immunity 1997, 7, 715-725) . Accordingly, the rate of receptor-mediated TRAF-2 consumption and TRAF-2 translation has been suggested to play a dynamic role in the regulation of cell survival (Duckett, C.S. and Thompson, C.B., Genes & Development 1997, 11, 2810-2821) . Targeted disruption of the TRAF-2 gene in mice has also been shown to generate severe defects in c-Jun N-terminal kinase ( NK) activation through TNFR1 (Yeh et al . , Immuni ty 1997, 7, 715-725). TRAF-2 (Rothe et al . , Science 1995, 269, 1424-1427), TRAF-3 (Cheng et al . , Science 1995, 267, 1494-1498), TRAF-5 (Ishida et al . , Proc . Natl Acad . Sci USA 1996, 93, 9437- 9442) and TRAF-6 (Pullen et al . , Biochemistry 1998, 37, 11836-11845) have also been shown to interact with the B lymphocyte receptor CD40. CD40 is a TNF receptor superfamily member that provides activation signals in antigen presenting cells such as B cells, macrophages and dendritic cells. Activation of CD40 leads to B-cell survival, growth and differentiation. In 293T cells, expression of TRAF-3 suppressed constitutive activity of NFKB, whereas expression of TRAF-5 induced NFKB activity. Targeted disruption of the TRAF-3 gene in mice causes impaired immune responses to T-dependent antigens and results in early postnatal lethality (Xu et al . , Immuni ty 1996, 5, 407-415) . TRAF-2, TRAF-5 or TRAF-6 overexpression in mammalian cells also induces JNK activation. TRAF-4 is expressed in breast cancers. In in vi tro binding assays, TRAF-4 has been shown to interact with the cytosolic domain of the lymphotoxin-β receptor (LTβR) and weakly with the p75 nerve growth factor receptor but not with TNFR1, TNFR2 , Fas or CD40 (Karjewska et al . , Am. J. of Pathol . 1998, 152, 6 , 1549-1561) . TRAF-6 has also been reported to mediate the signal transduction pathway induced by IL-1 to activate NFKB by recruiting IL-1 receptor associated kinase (IRAK) , a serine/threonine kinase (Cao et al . , Nature 1996 93:9437- 9442) . Thus, the role of TRAFs extends beyond being signal transducers for the TNF-receptor superfamily. The TRAF-5 protein and DNA encoding TRAF-5 are disclosed in O97/38099. Also disclosed in O97/38099 is an antisense oligonucleotide against the DNA, an anti-TRAF- 5 antibody, a vector containing the DNA, transformants containing this vector and methods of producing TRAF-5 with this vector. In addition, this PCT application discloses methods of screening substances binding to TRAF-5 and substances regulating the activity and expression of this protein. A TRAF family molecule, a polynucleotide coding for this molecule, an antibody against the molecule and an antisense polynucleotide of the molecule are also disclosed in WO97/31110. Disclosed in this PCT application are the base sequence of the gene and the amino acid of this "unknown" TRAF family molecule, which in addition to the antibody, are suggested to provide means for elucidating the functions of the proteins and the signal transducer system of a TNF-R family in which this molecule participates, to provide probes for research and diagnosis, and to indicate applications for therapeutic agents. Currently, however, there are no known therapeutic agents which effectively inhibit the synthesis of one or more selected TRAF family members. Consequently, there is a long-felt need for agents capable of effectively inhibiting TRAF expression. Antisense oligonucleotides against one or more TRAFs may therefore prove to be uniquely useful in a number of therapeutic, diagnostic and research applications. SUMMARY OF THE INVENTION The present invention is directed to antisense compounds, particularly oligonucleotides, which are targeted to a nucleic acid encoding a selected tumor necrosis factor receptor-associated factor (TRAF) , and which modulate the expression of the selected TRAF. Pharmaceutical and other compositions comprising the antisense compounds of the invention are also provided. Further provided are methods of modulating the expression of TRAFs in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of a selected TRAF by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention employs oligomeric antisense compounds, particularly oligonucleotides, for use in modulating the function of nucleic acid molecules encoding selected tumor necrosis factor receptor-associated factors (TRAFs) , ultimately modulating the amount of the selected TRAF produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding the selected TRAF. By "selected TRAF" it is meant any member of the TRAF family of proteins, most preferably TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5 or TRAF-6. As used herein, the terms "target nucleic acid" and "nucleic acid encoding TRAF" encompass DNA encoding a TRAF family member, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as "antisense" . The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of the selected TRAF. In the context of the present invention, "modulation" means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target. It is preferred to target specific nucleic acids for antisense. "Targeting" an antisense compound to a particular nucleic acid, in the context of this invention, is a multi-step process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is one or more nucleic acid molecules encoding one or more selected TRAFs. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5 ' -AUG (in transcribed mRNA molecules; 5 ' -ATG in the corresponding DNA molecule) , the translation initiation codon is also referred to as the "AUG codon," the "start codon" or the "AUG start codon" . A minority of genes have a translation initiation codon having the RNA sequence 5--GUG, 5' -UUG or 5'-CUG, and 5 ' -AUA, 5 ' -ACG and 5--CUG have been shown to function in vivo . Thus, the terms "translation initiation codon" and "start codon" can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes) . It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions . In the context of the invention, "start codon" and "translation initiation codon" refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding a TRAF, regardless of the sequence (s) of such codons . It is also known in the art that a translation termination codon (or "stop codon") of a gene may have one of three sequences, i.e., 5'-UAA, 5 ' -UAG and 5 ' -UGA (the corresponding DNA sequences are 5--TAA, 5 ' -TAG and 5 ' -TGA, respectively) . The terms "start codon region" and "translation initiation codon region" refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3 ' ) from a translation initiation codon. Similarly, the terms "stop codon region" and "translation termination codon region" refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5' or 3 ' ) from a translation termination codon. The open reading frame (ORF) or "coding region, " which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Other target regions include the 5' untranslated region (5'UTR), known in the art to refer to the portion of an mRNA in the 5 ' direction from the translation initiation codon, and thus including nucleotides between the 5' cap site and the translation initiation codon of an mRNA or corresponding nucleotides on the gene, and the 3' untranslated region (3'UTR), known in the art to refer to the portion of an mRNA in the 3 ' direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3 ' end of an mRNA or corresponding nucleotides on the gene. The 5' cap of an mRNA comprises an N7-methylated guanosine residue joined to the 5 ' -most residue of the mRNA via a 5 '-5' triphosphate linkage. The 5' cap region of an mRNA is considered to include the 5 ' cap structure itself as well as the first 50 nucleotides adjacent to the cap. The 5' cap region may also be a preferred target region. Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as "introns", which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as "exons" and are spliced together to form a continuous mRNA sequence. mRNA splice sites, i.e., intron-exon junctions, may also be preferred target regions, and are particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular mRNA splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. It has also been found that introns can also be effective, and therefore preferred, target regions for antisense compounds targeted, for example, to DNA or pre-mRNA. Once one or more target sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect. In the context of this invention, "hybridization" means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds . "Complementary, " as used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other. Thus, "specifically hybridizable" and "complementary" are terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. An antisense compound is specifically hybridizable when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA to cause a loss of utility, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, or in the case of in vi tro assays, under conditions in which the assays are performed. Antisense compounds are commonly used as research reagents and diagnostics. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes. Antisense compounds are also used, for example, to distinguish between functions of various members of a biological pathway. Antisense modulation has, therefore, been harnessed for research use. The specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. Antisense oligonucleotides have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that oligonucleotides can be useful therapeutic modalities that can be configured to be useful in treatment regimens in cells, tissues and animals, especially humans. In the context of this invention, the term "oligonucleotide" refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases. While antisense oligonucleotides are a preferred form of antisense compound, the present invention comprehends other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics such as are described below. The antisense compounds in accordance with this invention preferably comprise from about 8 to about 30 nucleobases. Particularly preferred are antisense oligonucleotides comprising from about 8 to about 30 nucleobases ( i . e. , from about 8 to about 30 linked nucleosides) . As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines . Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2', 3' or 5 ' hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn the respective ends of this linear polymeric structure can be further joined to form a circular structure, however, open linear structures are generally preferred. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3' to 5' phosphodiester linkage. Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides. Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkyl- phosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3 '-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates , thionoalkylphosphonates , thionoalkylphosphotriesters, and boranophosphates having normal 3 '-5' linkages, 2' -5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3 '-5' to 5' -3' or 2' -5' to 5' -2'. Various salts, mixed salts and free acid forms are also included. Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S.: 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897, 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131, 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677, 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111, 5,563,253; 5,571,799; 5,587,361; and 5,625,050, each of which is herein incorporated by reference. Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside) ; siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones ; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, 0, S and CH 2 component parts . Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S.: 5,034,506; 5,166,315; 5,185,444 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677, 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289, 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070, 5,663,312; 5,633,360; 5,677,437; and 5,677,439, each of which is herein incorporated by reference. In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA) . In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S.: 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al . , Science, 1991, 254, 1497-1500. Most preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular -CH 2 -NH-0-CH 2 - , -CH 2 -N (CH 3 ) -0-CH 2 - [known as a methylene (methylimino) or MMI backbone], -CH 2 -0-N(CH 3 ) -CH 2 - , -CH 2 -N(CH 3 ) -N(CH 3 ) -CH 2 - and -O-N (CH 3 ) -CH 2 -CH 2 - [wherein the native phosphodiester backbone is represented as -0-P-0-CH 2 -] of the above referenced U.S. Patent 5,489,677, and the amide backbones of the above referenced U.S. Patent 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Patent 5,034,506. Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2' position: OH; F; 0- , S-, or N-alkyl; 0-, S-, or N-alkenyl; 0-, S- or N- alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C_ to C 10 alkyl or C 2 to C 10 alkenyl and alkynyl . Particularly preferred are 0[(CH 2 ) n O] m CH 3 , 0(CH 2 ) n OCH 3 , 0(CH 2 ) n NH 2 , 0(CH 2 ) n CH 3 , 0(CH 2 ) n ONH 2 , and 0 (CH 2 ) n 0N[ (CH 2 ) n CH 3 ) ] 2 , where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2' position: C x to C 10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or 0- aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , S0CH 3 , S0 2 CH 3 , ON0 2 N0 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2 ' -methoxyethoxy (2 ' -0-CH 2 CH 2 OCH 3 , also known as 2 ' -0- (2 -methoxyethyl) or 2 '-MOE) (Martin et al . , Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2'- dimethylaminooxyethoxy, i.e., a 0 (CH 2 ) 2 ON(CH 3 ) 2 group, also known as 2 '-DMAOE, as described in United States patent application Serial Number 09/016,520, filed on January 30, 1998, which is commonly owned with the instant application and the contents of which are herein incorporated by reference. Other preferred modifications include 2 ' -methoxy (2'- 0-CH 3 ) , 2 ' -aminopropoxy (2 ' -OCH 2 CH 2 CH 2 NH 2 ) and 2 '-fluoro (2'- F) . Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3' position of the sugar on the 3 ' terminal nucleotide or in 2' -5' linked oligonucleotides and the 5' position of 5' terminal nucleotides. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811, 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5 , 700 , 920 , each of which is incorporated herein by reference. Oligonucleotides may also include nucleobase (often referred to in the art simply as "base") modifications or substitutions. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G) , and the pyrimidine bases thymine (T) , cytosine (C) and uracil (U) . Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-Me-C) , 5-hydroxymethyl cytosine, xanthine, hypoxanthine , 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2- thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil) , 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8- thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7- methylguanine and 7-methyladenine, 8-azaguanine and 8- azaadenine, 7-deazaguanine and 7-deazaadenine and 3- deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in U.S. Patent 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J. I. , ed. John Wiley & Sons, 1990, those disclosed by Englisch et al . , Angewandte Chemie, International Edition, 1991, 30 , 613, and those disclosed by Sanghvi, Y.S., Crooke, S.T. and Lebleu, B. eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 289-302. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6- azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5- propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2°C (Sanghvi, Y.S., Crooke, S.T. and Lebleu, B., eds., Antisense Research and Applications, CRC Press, Boca Raton, 1993, pp. 276-278) and are presently preferred base substitutions, even more particularly when combined with 2 ' -O-methoxyethyl sugar modifications. Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, U.S.: 3,687,808; 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711, 5,552,540; 5,587,469; 5,594,121; 5,596,091; 5,614,617, 5,681,941; and 5,750,692, each of which is herein incorporated by reference. Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al . , Proc . Natl . Acad . Sci . USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al . , Bioorg. Med. Chem . Let . , 1994, 4, 1053-1060), a thioether, e . g. , hexyl- S-tritylthiol (Manoharan et al . , Ann . N. Y. Acad . Sci . , 1992, 660, 306-309; Manoharan et al . , Bioorg. Med. Chem. Let . , 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl . Acids Res . , 1992, 20, 533-538), an aliphatic chain, e . g. , dodecandiol or undecyl residues (Saison- Behmoaras et al . , EMBO J. , 1991, 10, 1111-1118; Kabanov et al., FEBS Lett . , 1990, 259, 327-330; Svinarchuk et al . , Biochimie, 1993, 75, 49-54), a phospholipid, e . g. , di- hexadecyl-rac-glycerol or triethylammonium 1,2-di-O- hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al . , Tetrahedron Lett . , 1995, 36, 3651-3654; Shea et al . , Nucl . Acids Res . , 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973) , or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys . Acta, 1995, 1264, 229-237) , or an octadecylamine or hexylamino- carbonyl-oxycholesterol moiety (Crooke et al . , J. Pharmacol . Exp . Ther. , 1996, 277, 923-937. Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S.: 4,828,979; 4,948,882; 5,218,105; 5,525,465 5,541,313 5,545,730 5,552,538 5,578,717 5,580,731 5,580,731 5,591,584 5,109,124 5,118,802 5,138,045 5,414,077 5,486,603 5,512,439 5,578,718 5,608,046 4,587,044 4,605,735 4,667,025 4,762,779 4,789,737 4,824,941 4,835,263 4,876,335 4,904,582 4,958,013 5,082,830 5,112,963 5,214,136 5,082,830 5,112,963 5,214,136 5,245,022 5,254,469 5,258,506 5,262,536 5,272,250 5,292,873 5,317,098 5,371,241 5,391,723 5,416,203 5,451,463 5,510,475 5,512,667 5,514,785 5,565,552 5,567,810 5,574,142 5,585,481 5,587,371 5,595,726 5,597,696 5,599,923 5,599, 928 and 5,688,941 each of which is herein incorporated by reference. It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. The present invention also includes antisense compounds which are chimeric compounds. "Chimeric" antisense compounds or "chimeras," in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNase H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art . Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers . Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S.: 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, each of which is herein incorporated by reference. The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, CA) . Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives. The antisense compounds of the invention are synthesized in vi tro and do not include antisense compositions of biological origin, or genetic vector constructs designed to direct the in vivo synthesis of antisense molecules. The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption assisting formulations include, but are not limited to, U.S.: 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291, 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330, 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170, 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978, 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259, 5,543,152; 5,556,948; 5,580,575; and 5 , 595 , 756 , each of which is herein incorporated by reference. The antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents . The term "prodrug" indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [ (S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93/24510 or in WO 94/26764. The term "pharmaceutically acceptable salts" refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto (see, for example, Berge et al . , "Pharmaceutical Salts," J. of Pharma Sci . , 1977, 66, 1-19). For oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine . The antisense compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of one or more members of the TRAF family is treated by administering antisense compounds in accordance with this invention. The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an antisense compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the antisense compounds and methods of the invention may also be useful prophylactically, e . g. , to prevent or delay infection, inflammation or tumor formation, for example. The antisense compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding one or more selected TRAFs, enabling sandwich and other assays to easily be constructed to exploit this fact. Hybridization of the antisense oligonucleotides of the invention with a nucleic acid encoding one or more TRAFs can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of TRAF in a sample may also be prepared. The present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e . g. , by inhalation or insufflation of powders or aerosols, including by nebulizer; (intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2 ■ -O-methoxyethyl modification are believed to be particularly useful for oral administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients. For example, pharmaceutical compositions and/or formulations comprising the oligonucleotides of the present invention may include penetration enhancers in order to enhance the alimentary delivery of the oligonucleotides. Penetration enhancers may be classified as belonging to one of five broad categories, i.e., fatty acids, bile salts, chelating agents, surfactants and non-surfactants (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems, 1991, 8, 91-192; Muranishi, Cri tical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1-33). One or more penetration enhancers from one or more of these broad categories may be included. Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, recinleate, monoolein (a.k.a. 1-monooleoyl-rac- glycerol) , dilaurin, caprylic acid, arachidonic acid, glyceryl 1-monocaprate, l-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, mono- and di-glycerides and physiologically acceptable salts thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems, 1991, 8, 2, 91-192; Muranishi, Cri tical Reviews in Therapeutic Drug Carrier Systems, 1990, 7, 1, 1-33; El-Hariri et al . , J " . Pharm . Pharmacol . , 1992, 44, 651-654). Examples of some presently preferred fatty acids are sodium caprate and sodium laurate, used singly or in combination at concentrations of 0.5 to 5%. The physiological roles of bile include the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 In: Goodman & Gilman ' s The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al . , eds., McGraw-Hill, New York, NY, 1996, pages 934-935) . Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus, the term "bile salt" includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. Regardless of the method by which the antisense compounds of the invention are introduced into a patient, colloidal dispersion systems may be used as delivery vehicles to enhance the in vivo stability of the compounds and/or to target the compounds to a particular organ, tissue or cell type. Colloidal dispersion systems include, but are not limited to, macromolecule complexes, nanocapsules, microspheres, beads and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, liposomes and lipid:oligonucleotide complexes of uncharacterized structure. A preferred colloidal dispersion system is a plurality of liposomes. Liposomes are microscopic spheres having an aqueous core surrounded by one or more outer layer (s) made up of lipids arranged in a bilayer configuration (see, generally, Chonn et al . , Current Op . Biotech . , 1995, 6, 698-708). Liposome preparation is described in pending United States patent application 08/961,469, filed on October 31, 1997, which is commonly owned with the instant application and which is herein incorporated by reference. Certain embodiments of the invention provide for liposomes and other compositions containing (a) one or more antisense compounds and (b) one or more other chemotherapeutic agents which function by a non-antisense mechanism. Other non-antisense chemotherapeutic agents are also within the scope of this invention. Two or more combined compounds may be used together or sequentially. In another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Two or more combined compounds may be used together or sequentially. The formulation of therapeutic compositions and their subsequent administration is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates . Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC 50 s found to be effective in in vi tro and in vivo animal models. In general, dosage is from 0.01 μg to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 μg to 100 g per kg of body weight, once or more daily, to once every 20 years. While the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same. EXAMPLES Example 1 Nucleoside Phosphoramidites for Oligonucleotide Synthesis Deoxy and 2' -alkoxy amidites 2 '-Deoxy and 2'-methoxy beta-cyanoethyldiisopropyl phosphoramidites are purchased from commercial sources ( e . g. , Chemgenes, Needham, MA or Glen Research, Inc. Sterling VA) . Other 2'-0-alkoxy substituted nucleoside amidites are prepared as described in U.S. Patent 5,506,351, herein incorporated by reference. For oligonucleotides synthesized using 2' -alkoxy amidites, the standard cycle for unmodified oligonucleotides is utilized, except the wait step after pulse delivery of tetrazole and base is increased to 360 seconds. Oligonucleotides containing 5-methyl-2 ■ -deoxycytidine (5-Me-C) nucleotides were synthesized according to published methods (Sanghvi, et . al . , Nucleic Acids Research, 1993, 21, 3197-3203] using commercially available phosphoramidites (Glen Research, Sterling VA or ChemGenes, Needham, MA) . 2 '-Fluoro amidites 2' -Fluorodeoxyadenosine amidites 2 '-fluoro oligonucleotides are synthesized as described previously by Kawasaki, et . al., J. Med . Chem . , 1993, 36, 831-841 and U.S. Patent 5,670,633, herein incorporated by reference. Briefly, the protected nucleoside N6-benzoyl-2 ' -deoxy-2 ' -fluoroadenosine are synthesized utilizing commercially available 9-beta-D- arabinofuranosyladenine as starting material and by modifying literature procedures whereby the 2 ' -alpha-fluoro atom is introduced by a S N 2-displacement of a 2 ' -beta-trityl group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine is selectively protected in moderate yield as the 3 ' , 5 ' - ditetrahydropyranyl (THP) intermediate. Deprotection of the THP and N6-benzoyl groups is accomplished using standard methodologies and standard methods are used to obtain the 5 ' -dimethoxytrityl- (DMT) and 5 ' -DMT-3 ' - phosphoramidite intermediates . 2 ' -Fluorodeoxyguanosine The synthesis of 2 ' -deoxy-2 ' -fluoroguanosine is accomplished using tetraisopropyldisiloxanyl (TPDS) protected 9-beta-D-arabinofuranosylguanine as starting material, and conversion to the intermediate diisobutyryl- arabinofuranosylguanosine. Deprotection of the TPDS group is followed by protection of the hydroxyl group with THP to give diisobutyryl di-THP protected arabinofuranosylguanine . Selective O-deacylation and triflation is followed by treatment of the crude product with fluoride, then deprotection of the THP groups . Standard methodologies are used to obtain the 5 ' -DMT- and 5 ' -DMT-3 ' -phosphoramidites . 2' -Fluorouridine Synthesis of 2 ' -deoxy-2 ' -fluorouridine is accomplished by the modification of a literature procedure in which 2 , 2 ' -anhydro-1-beta-D-arabinofuranosyluracil is treated with 70% hydrogen fluoride-pyridine . Standard procedures are used to obtain the 5 ' -DMT and 5'-DMT- 3 ' phosphoramidites . 2 ' -Fluorodeoxycytidine 2 ' -deoxy-2 ' -fluorocytidine is synthesized via amination of 2 ' -deoxy-2 ' -fluorouridine, followed by selective protection to give N4 -benzoyl-2 ' -deoxy-2 ' - fluorocytidine. Standard procedures are used to obtain the 5 ' -DMT and 5 ' -DMT-3 'phosphoramidites . 2' -O- (2-Methoxyethyl) modified amidites 2 ' -O-Methoxyethyl-substituted nucleoside amidites were prepared as follows, or alternatively, as per the methods of Martin, P., Helvetica Chimica Acta, 1995, 78, 486-504. 2,2 ' -Anhydro [1- (beta-D-arabinofuranosyl) -5- ethyluridine] 5-Methyluridine (ribosylthymine, commercially available through Yamasa, Choshi, Japan) (72.0 g, 0.279 M) , diphenylcarbonate (90.0 g, 0.420 M) and sodium bicarbonate (2.0 g, 0.024 M) were added to DMF (300 mL) . The mixture was heated to reflux, with stirring, allowing the evolved carbon dioxide gas to be released in a controlled manner. After 1 hour, the slightly darkened solution was concentrated under reduced pressure. The resulting syrup was poured into diethylether (2.5 L) , with stirring. The product formed a gum. The ether was decanted and the residue was dissolved in a minimum amount of methanol (ca. 400 mL) . The solution was poured into fresh ether (2.5 L) to yield a stiff gum. The ether was decanted and the gum dried in a vacuum oven (60°C at 1 mm Hg for 24 hours) to give a solid that was crushed to a light tan powder (57 g, 85% crude yield) . The NMR spectrum was consistent with the structure, contaminated with phenol as its sodium salt (ca. 5%) . The material was used as is for further reactions (or purified further by column chromatography using a gradient of methanol in ethyl acetate (10-25%) to give a white solid, mp 222-4°C) . 2 ' -O-Methoxyethyl-5-methyluridine 2,2 ' -Anhydro-5-methyluridine (195 g, 0.81 M), tris(2- methoxyethyl) borate (231 g, 0.98 M) and 2-methoxyethanol (1.2 L) were added to a 2 L stainless steel pressure vessel and placed in a pre-heated oil bath at 160°C. After heating for 48 hours at 155-160°C, the vessel was opened and the solution evaporated to dryness and triturated with MeOH (200 mL) . The residue was suspended in hot acetone (1 L) . The insoluble salts were filtered, washed with acetone (150 mL) and the filtrate evaporated. The residue (280 g) was dissolved in CH 3 CN (600 mL) and evaporated. A silica gel column (3 kg) was packed in CH 2 Cl 2 /Acetone/MeOH (20:5:3) containing 0.5% Et 3 NH. The residue was dissolved in CH 2 C1 2 (250 mL) and adsorbed onto silica (150 g) prior to loading onto the column. The product was eluted with the packing solvent to give 160 g (63%) of product. Additional material was obtained by reworking impure fractions. 2 ' -O-Methoxyethyl-5 • -O-dimethoxytrityl-5-methyluridine 2 ' -O-Methoxyethyl-5-methyluridine (160 g, 0.506 M) was co-evaporated with pyridine (250 mL) and the dried residue dissolved in pyridine (1.3 L) . A first aliquot of dimethoxytrityl chloride (94.3 g, 0.278 M) was added and the mixture stirred at room temperature for one hour. A second aliquot of dimethoxytrityl chloride (94.3 g, 0.278 M) was added and the reaction stirred for an additional one hour. Methanol (170 mL) was then added to stop the reaction. HPLC showed the presence of approximately 70% product. The solvent was evaporated and triturated with CH 3 CN (200 mL) . The residue was dissolved in CHC1 3 (1.5 L) and extracted with 2x500 mL of saturated NaHC0 3 and 2x500 mL of saturated NaCl. The organic phase was dried over Na 2 S0 4 , filtered and evaporated. The residue was purified on a 3.5 kg silica gel column, packed and eluted with EtOAc/Hexane/Acetone (5:5:1) containing 0.5% Et 3 NH. The pure fractions were evaporated to give 164 g of product. Approximately 20 g additional was obtained from the impure fractions to give a total yield of 183 g (57%) . 3 ' -O-Acetyl-2 ' -O-methoxyethyl-5 ' -0-dimethoxytrityl-5- methyluridine 2 ' -O-Methoxyethyl-5 ' -0-dimethoxytrityl-5-methyluridine (106 g, 0.167 M) , DMF/pyridine (750 mL of a 3:1 mixture prepared from 562 mL of DMF and 188 mL of pyridine) and acetic anhydride (24.38 mL, 0.258 M) were combined and stirred at room temperature for 24 hours. The reaction was monitored by tic by first quenching the tic sample with the addition of MeOH. Upon completion of the reaction, as judged by tic, MeOH (50 mL) was added and the mixture evaporated at 35°C. The residue was dissolved in CHC1 3 (800 mL) and extracted with 2x200 mL of saturated sodium bicarbonate and 2x200 mL of saturated NaCl. The water layers were back extracted with 200 mL of CHC1 3 . The combined organics were dried with sodium sulfate and evaporated to give 122 g of residue (approx. 90% product) . The residue was purified on a 3.5 kg silica gel column and eluted using EtOAc/Hexane (4 : 1) . Pure product fractions were evaporated to yield 96 g (84%). An additional 1.5 g was recovered from later fractions. 3 ' -O-Acetyl-2 1 -O-methoxyethyl-5 1 -O-dimethoxytrityl-5- methyl-4-triazoleuridine A first solution was prepared by dissolving 3 ' -0- acetyl-2 ■ -O-methoxyethyl-5 ' -O-dimethoxytrityl-5- methyluridine (96 g, 0.144 M) in CH 3 CN (700 mL) and set aside. Triethylamine (189 mL, 1.44 M) was added to a solution of triazole (90 g, 1.3 M) in CH 3 CN (1 L) , cooled to -5°C and stirred for 0.5 hours using an overhead stirrer. P0C1 3 was added dropwise, over a 30 minute period, to the stirred solution maintained at 0-10°C, and the resulting mixture stirred for an additional 2 hours. The first solution was added dropwise, over a 45 minute period, to the latter solution. The resulting reaction mixture was stored overnight in a cold room. Salts were filtered from the reaction mixture and the solution evaporated. The residue was dissolved in EtOAc (1 L) and the insoluble solids removed by filtration. The filtrate was washed with 1x300 mL of NaHC0 3 and 2x300 mL of saturated NaCl, dried over sodium sulfate and evaporated. The residue was triturated with EtOAc to give the title compound. 2 ' -O-Methoxyethyl-5 ' -O-dimethoxytrityl-5- methylcytidine A solution of 3 ' -O-acetyl-2 ' -O-methoxyethyl-5 ' -0- dimethoxytrityl-5-methyl-4-triazoleuridine (103 g, 0.141 M) in dioxane (500 mL) and NH 4 0H (30 mL) was stirred at room temperature for 2 hours. The dioxane solution was evaporated and the residue azeotroped with MeOH (2x200 mL) . The residue was dissolved in MeOH (300 mL) and transferred to a 2 liter stainless steel pressure vessel. MeOH (400 mL) saturated with NH 3 gas was added and the vessel heated to 100°C for 2 hours (tic showed complete conversion) . The vessel contents were evaporated to dryness and the residue was dissolved in EtOAc (500 mL) and washed once with saturated NaCl (200 mL) . The organics were dried over sodium sulfate and the solvent evaporated to give 85 g (95%) of the title compound. N4-Benzoyl-2 ' -O-methoxyethyl-5 ' -O-dimethoxytrityl-5- methylcytidine 2 ' -O-Methoxyethyl-5 ' -O-dimethoxytrityl-5-methyl- cytidine (85 g, 0.134 M) was dissolved in DMF (800 mL) and benzoic anhydride (37.2 g, 0.165 M) is added with stirring. The mixture was stirred for 3 hours (tic showing the reaction to be approximately 95% complete) . The solvent was evaporated and the residue azeotroped with MeOH (200 mL) . The residue was then dissolved in CHC1 3 (700 mL) and extracted with saturated NaHC0 3 (2x300 mL) and saturated NaCl (2x300 mL) , dried over MgS0 4 and evaporated to give a residue (96 g) . The residue was chromatographed on a 1.5 kg silica column using EtOAc/Hexane (1:1) containing 0.5% Et 3 NH as the eluting solvent. The pure product fractions were evaporated to give 90 g (90%) of the title compound. N4-Benzoyl-2 ' -O-methoxyethyl-5 ' -O-dimethoxytrityl-5- methylcytidine-3 * -amidite N4-Benzoyl-2 ' -O-methoxyethyl-5 ' -0-dimethoxytrityl-5- methylcytidine (74 g, 0.10 M) was dissolved in CH 2 C1 2 (1 L) . Tetrazole diisopropylamine (7.1 g) and 2-cyanoethoxy-tetra- (isopropyl) phosphite (40.5 mL, 0.123 M) were added with stirring, under a nitrogen atmosphere. The resulting mixture was stirred for 20 hours at room temperature (tic showing the reaction to be 95% complete) . The reaction mixture was extracted with saturated NaHC0 3 (1x300 mL) and saturated NaCl (3x300 mL) . The aqueous washes were back- extracted with CH 2 C1 2 (300 mL) , and the extracts were combined, dried over MgS0 4 and concentrated. The residue obtained was chromatographed on a 1.5 kg silica column using EtOAc/Hexane (3:1) as the eluting solvent. The pure fractions were combined to give 90.6 g (87%) of the title compound. 2' - (Aminooxyethyl) nucleoside amidites and 2'- (dimethylaminooxyethy1) nucleoside amidites Aminooxyethyl and dimethylaminooxyethyl amidites are prepared as per the methods described in United States patent applications serial number 10/037,143, filed February 14, 1998, and serial number 09/016,520, filed January 30, 1998, each of which is herein incorporated by reference. Example 2 Oligonucleotide synthesis Unsubstituted and substituted phosphodiester (P=0) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 380B) using standard phosphoramidite chemistry with oxidation by iodine. Phosphorothioates (P=S) were synthesized as for the phosphodiester oligonucleotides except the standard oxidation bottle was replaced by 0.2 M solution of 3H-1,2- benzodithiole-3-one 1,1-dioxide in acetonitrile for the stepwise thiation of the phosphite linkages. The thiation wait step was increased to 68 seconds and was followed by the capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55°C (18 hours) , the oligonucleotides were purified by precipitating twice with 2.5 volumes of ethanol from a 0.5 M NaCl solution. Phosphinate oligonucleotides are prepared as described in U.S. Patent 5,508,270, herein incorporated by reference. Alkyl phosphonate oligonucleotides are prepared as described in U.S. Patent 4,469,863, herein incorporated by reference. 3 ' -Deoxy-3' -methylene phosphonate oligonucleotides are prepared as described in U.S. Patents 5,610,289 or 5,625,050, herein incorporated by reference. Phosphoramidite oligonucleotides are prepared as described in U.S. Patent, 5,256,775 or U.S. Patent 5,366,878, herein incorporated by reference. Alkylphosphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (published as WO 94/17093 and WO 94/02499, respectively), herein incorporated by reference. 3 ' -Deoxy-3 ' -amino phosphoramidate oligonucleotides are prepared as described in U.S. Patent 5,476,925, herein incorporated by reference. Phosphotriester oligonucleotides are prepared as described in U.S. Patent 5,023,243, herein incorporated by reference. Borano phosphate oligonucleotides are prepared as described in U.S. Patents 5,130,302 and 5,177,198, herein incorporated by reference. Example 3 Oligonucleoside Synthesis Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedi- methylhydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligo- nucleosides, also identified as amide-4 linked oligonucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and P=0 or P=S linkages are prepared as described in U.S. Patents 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference. Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Patents 5,264,562 and 5,264,564, herein incorporated by reference. Ethylene oxide linked oligonucleosides are prepared as described in U.S. Patent 5,223,618, herein incorporated by reference. Example 4 PNA Synthesis Peptide nucleic acids (PNAs) are prepared in accordance with any of the various procedures referred to in Peptide Nucleic Acids (PNA) : Synthesis, Properties and Potential Applications, Bioorganic & Medicinal Chemistry, 1996, 4, 5-23. They may also be prepared in accordance with U.S. Patents 5,539,082, 5,700,922, and 5,719,262, herein incorporated by reference. Example 5 Synthesis of Chimeric Oligonucleotides Chimeric oligonucleotides, oligonucleosides or mixed oligonucleotides/oligonucleosides of the invention can be of several different types. These include a first type wherein the "gap" segment of linked nucleosides is positioned between 5' and 3' "wing" segments of linked nucleosides and a second "open end" type wherein the "gap" segment is located at either the 3' or the 5' terminus of the oligomeric compound. Oligonucleotides of the first type are also known in the art as "gapmers" or gapped oligonucleotides. Oligonucleotides of the second type are also known in the art as "hemimers" or "wingmers". [2 ' -O-Me] - - [2 • -deoxy] - - [2 ' -O-Me] Chimeric Phosphorothioate Oligonucleotides Chimeric oligonucleotides having 2'-0-alkyl phosphorothioate and 2 ' -deoxy phosphorothioate oligo- nucleotide segments are synthesized using an Applied Biosystems automated DNA synthesizer Model 380B, as above. Oligonucleotides are synthesized using the automated synthesizer and 2' -deoxy-5 ' -dimethoxytrityl-3 ' -O-phosphoramidite for the DNA portion and 5 ' -dimethoxytrityl-2 ' -0- methyl-3 ' -O-phosphoramidite for 5' and 3' wings. The standard synthesis cycle is modified by increasing the wait step after the delivery of tetrazole and base to 600 seconds repeated four times for RNA and twice for 2 ' -O- methyl . The fully protected oligonucleotide is cleaved from the support and the phosphate group is deprotected in 3 : 1 Ammonia/Ethanol at room temperature overnight then lyophilized to dryness. Treatment in methanolic ammonia for 24 hours at room temperature is then done to deprotect all bases and sample was again lyophilized to dryness. The pellet is resuspended in IM TBAF in THF for 24 hours at room temperature to deprotect the 2' positions. The reaction is then quenched with IM TEAA and the sample is then reduced to 1/2 volume by rotovac before being desalted on a G25 size exclusion column. The oligo recovered is then analyzed spectrophotometrically for yield and for purity by capillary electrophoresis and by mass spectrometry. [2'-0- (2-Methoxyethyl)] -- [2 ' -deoxy] -- [2 • -O- (Methoxyethyl) ] Chimeric Phosphorothioate Oligonucleotides [2 ' -0- (2-methoxyethyl) ] -- [2 ' -deoxy] -- [-2 ' -0- (methoxyethyl) ] chimeric phosphorothioate oligonucleotides were prepared as per the procedure above for the 2'-0-methyl chimeric oligonucleotide, with the substitution of 2'-0- (methoxyethyl) amidites for the 2'-0-methyl amidites. [2 ' -O- (2-Methoxyethyl) hosphodiester] -- [2 ' -deoxy Phosphorothioate] -- [2 ' -O- (2-Methoxyethyl) Phosphodiester] Chimeric Oligonucleotides [2 ' -0- (2-methoxyethyl phosphodiester] -- [2 ' -deoxy phos- phorothioate] -- [2 ' -0- (methoxyethyl) phosphodiester] chimeric oligonucleotides were prepared as per the above procedure for the 2'-0-methyl chimeric oligonucleotide with the substitution of 2' -0- (methoxyethyl) amidites for the 2'-0-methyl amidites, oxidization with iodine to generate the phosphodiester internucleotide linkages within the wing portions of the chimeric structures and sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) to generate the phosphorothioate internucleotide linkages for the center gap. Other chimeric oligonucleotides, chimeric oligonucleosides and mixed chimeric oligonucleotides/oligonucleosides are synthesized according to United States patent 5,623,065, herein incorporated by reference. Example 6 Oligonucleotide Isolation After cleavage from the controlled pore glass column (Applied Biosystems) and deblocking in concentrated ammonium hydroxide at 55°C for 18 hours, the oligonucleotides or oligonucleosides were purified by precipitation twice out of 0.5 M NaCl with 2.5 volumes ethanol . Synthesized oligonucleotides were analyzed by polyacrylamide gel electrophoresis on denaturing gels and judged to be at least 85% full length material. The relative amounts of phosphorothioate and phosphodiester linkages obtained in synthesis were periodically checked by 31 P nuclear magnetic resonance spectroscopy, and for some studies oligonucleotides are purified by HPLC, as described by Chiang et al . , J " . Biol . Chem. 1991, 266, 18162-18171. Results obtained with HPLC-purified material are similar to those obtained with non-HPLC purified material. Example 7 Oligonucleotide Synthesis - 96 Well Plate Format Oligonucleotides were synthesized via solid phase P(III) phosphoramidite chemistry on an automated synthesizer capable of assembling 96 sequences simultaneously in a standard 96 well format. Phosphodiester internucleotide linkages were afforded by oxidation with aqueous iodine. Phosphorothioate internucleotide linkages were generated by sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) in anhydrous acetonitrile. Standard base- protected beta-cyanoethyldiisopropyl phosphoramidites were purchased from commercial vendors ( e . g. PE-Applied Biosystems, Foster City, CA, or Pharmacia, Piscataway, NJ) . Non-standard nucleosides were synthesized as per known literature or patented methods. They were utilized as base protected beta-cyanoethyldiisopropyl phosphoramidites. Oligonucleotides were cleaved from support and deprotected with concentrated NH 4 OH at elevated temperature (55-60°C) for 12-16 hours and the released product then dried in vacuo. The dried product was then re-suspended in sterile water to afford a master plate from which all analytical and test plate samples were then diluted utilizing robotic pipettors . Example 8 Oligonucleotide Analysis - 96 Well Plate Format The concentration of oligonucleotide in each well was assessed by dilution of samples and UV absorption spectroscopy. The full-length integrity of the individual products was evaluated by capillary electrophoresis (CE) in either the 96 well format (Beckman P/ACE™ MDQ) or, for individually prepared samples, on a commercial CE apparatus ( e . g. , Beckman P/ACE™ 5000, ABI 270). Base and backbone composition was confirmed by mass analysis of the compounds utilizing electrospray-mass spectroscopy. All assay test plates were diluted from the master plate using single and multi-channel robotic pipettors. Plates were judged to be acceptable if at least 85% of the compounds on the plate were at least 85% full length. Example 9 Cell culture and oligonucleotide treatment The effect of antisense compounds on target nucleic acid expression can be tested in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. This can be routinely determined using, for example, PCR, RNAse protection assay (RPA) or Northern blot analysis. The following four cell types are provided for illustrative purposes, but other cell types can be routinely used. T- 24 cells : The transitional cell bladder carcinoma cell line T-24 is obtained from the American Type Culture Collection (ATCC) (Manassas, VA) . T-24 cells are routinely cultured in complete McCoy's 5A basal media (Gibco/Life Technologies, Gaithersburg, MD) supplemented with 10% fetal calf serum (Gibco/Life Technologies, Gaithersburg, MD) , penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Gibco/Life Technologies, Gaithersburg, MD) . Cells are routinely passaged by trypsinization and dilution when they reached 90% confluence. Cells are seeded into 96-well plates (Falcon-Primaria #3872) at a density of 7000 cells/well for use in RT-PCR analysis. For Northern blotting or other analysis, cells may be seeded onto 100 mm or other standard tissue culture plates and treated similarly, using appropriate volumes of medium and oligonucleotide. A549 cells: The human lung carcinoma cell line A549 is obtained from the American Type Culture Collection (ATCC) (Manassas, VA) . A549 cells are routinely cultured in DMEM basal media (Gibco/Life Technologies, Gaithersburg, MD) supplemented with 10% fetal calf serum (Gibco/Life Technologies, Gaithersburg, MD) , penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Gibco/Life Technologies, Gaithersburg, MD) . Cells are routinely passaged by trypsinization and dilution when they reach 90% confluence. NHDF cells: Human neonatal dermal fibroblast (NHDF) are obtained from the Clonetics Corporation (Walkersville MD) . NHDFs are routinely maintained in Fibroblast Growth Medium (Clonetics Corporation, Walkersville, MD) supplemented as recommended by the supplier. Cells are maintained for up to 10 passages as recommended by the supplier. HEK cells: Human embryonic keratinocytes (HEK) are obtained from the Clonetics Corporation (Walkersville, MD) . HEKs are routinely maintained in Keratinocyte Growth Medium (Clonetics Corporation, Walkersville, MD) formulated as recommended by the supplier. Cells are routinely maintained for up to 10 passages as recommended by the supplier. Treatment with antisense compounds : When cells reach 80% confluency, they are treated with oligonucleotide. For cells grown in 96-well plates, wells are washed once with 200 μL 0PTI-MEM™-1 reduced-serum medium (Gibco BRL) and then treated with 130 μL of OPTI- MEM™-! containing 3.75 μg/mL LIPOFECTIN™ (Gibco BRL) and the desired oligonucleotide at a final concentration of 150 nM. After 4 hours of treatment, the medium is replaced with fresh medium. Cells are harvested 16 hours after oligonucleotide treatment. Example 10 Analysis of oligonucleotide inhibition of TRAF expression Antisense modulation of TRAF expression can be assayed in a variety of ways known in the art. For example, TRAF mRNA levels can be quantitated by, e . g. , Northern blot analysis, RNAse protection assay (RPA) , competitive polymerase chain reaction (PCR) , or real-time PCR (RT-PCR) . RNA analysis can be performed on total cellular RNA or poly (A) + mRNA. Methods of RNA isolation are taught in, for example, Ausubel, et al., Current Protocols in Molecular Biology, Volume 1, John Wiley & Sons, Inc., 1993, pp. 4.1.1-4.2.9 and 4.5.1-4.5.3. Northern blot analysis is routine in the art and is taught in, for example, Ausubel, et al . , Current Protocols in Molecular Biology, Volume 1, John Wiley & Sons, Inc., 1996, pp. 4.2.1-4.2.9. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available ABI PRISM™ 7700 Sequence Detection System, available from PE-Applied Biosystems, Foster City, CA and used according to manufacturer's instructions. Other methods of PCR are also known in the art . TRAF protein levels can be quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting) , ELISA or fluorescence-activated cell sorting (FACS) . Antibodies directed to TRAF can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, MI) , or can be prepared via conventional antibody generation methods. Methods for preparation of polyclonal antisera are taught in, for example, Ausubel, et al., Current Protocols in Molecular Biology, Volume 2, John Wiley & Sons, Inc., 1997, pp. 11.12.1-11.12.9. Preparation of monoclonal antibodies is taught in, for example, Ausubel, et al . , Current Protocols in Molecular Biology, Volume 2, John Wiley & Sons, Inc., 1997, pp. 11.4.1-11.11.5. Immunoprecipitation methods are standard in the art and can be found at, for example, Ausubel, et al., Current Protocols in Molecular Biology, Volume 2, John Wiley & Sons, Inc., 1998, pp. 11.4.1-11.11.5. Western blot (immunoblot) analysis is standard in the art and can be found at, for example, Ausubel, et al . , Current Protocols in Molecular Biology, Volume 2, John Wiley & Sons, Inc., 1997, pp. 10.8.1-10.8.21. Enzyme-linked immunosorbent assays (ELISA) are standard in the art and can be found at, for example, Ausubel, et al . , Current Protocols in Molecular Biology, Volume 2, John Wiley & Sons, Inc., 1991, pp. 11.2.1-11.2.22. Example 11 Poly (A) + mRNA isolation Poly (A) + mRNA is isolated according to Miura et al . , Clin . Chem. , 1996, 42, 1758-1764. Other methods for poly (A) + mRNA isolation are taught in, for example, Ausubel, et al . , Current Protocols in Molecular Biology, Volume 1, John Wiley & Sons, Inc., 1993, pp. 4.5.1-4.5.3. Briefly, for cells grown on 96-well plates, growth medium is removed from the cells and each well is washed with 200 μL cold PBS. 60 μL lysis buffer (10 mM Tris-HCl, pH 7.6, 1 mM EDTA, 0.5 M NaCl, 0.5% NP-40, 20 mM vanadyl- ribonucleoside complex) is added to each well, the plate is gently agitated and then incubated at room temperature for 5 minutes. 55 μL of lysate is transferred to Oligo d(T) coated 96-well plates (AGCT Inc., Irvine, CA) . Plates are incubated for 60 minutes at room temperature, washed 3 times with 200 μL of wash buffer (10 mM Tris-HCl pH 7.6 , 1 mM EDTA, 0.3 M NaCl) . After the final wash, the plate is blotted on paper towels to remove excess wash buffer and then air-dried for 5 minutes. 60 μL of elution buffer (5 mM Tris-HCl pH 7.6), preheated to 70°C is added to each well, the plate is incubated on a 90°C hot plate for 5 minutes, and the eluate is then transferred to a fresh 96-well plate. Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions. Example 12 Total RNA Isolation Total mRNA was isolated using an RNEASY 96™ kit and buffers purchased from Qiagen Inc. (Valencia, CA) following the manufacturer's recommended procedures. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 100 μL Buffer RLT was added to each well and the plate vigorously agitated for 20 seconds. 100 μL of 70% ethanol was then added to each well and the contents mixed by pipetting three times up and down. The samples were then transferred to the RNEASY 96™ well plate attached to a QIAVAC™ manifold fitted with a waste collection tray and attached to a vacuum source. Vacuum was applied for 15 seconds. 1 mL of Buffer RW1 was added to each well of the RNEASY 96™ plate and the vacuum again applied for 15 seconds. 1 mL of Buffer RPE was then added to each well of the RNEASY 96™ plate and the vacuum applied for a period of 15 seconds. The Buffer RPE wash was then repeated and the vacuum was applied for an additional 10 minutes. The plate was then removed from the QIAVAC™ manifold and blotted dry on paper towels. The plate was then re-attached to the QIAVAC™ manifold fitted with a collection tube rack containing 1.2 mL collection tubes. RNA was then eluted by pipetting 60 μL water into each well, incubating 1 minute, and then applying the vacuum for 30 seconds. The elution step was repeated with an additional 60 μL water. Example 13 Real-time Quantitative PCR Analysis of TRAF mRNA Levels Quantitation of TRAF mRNA levels is determined by real-time quantitative PCR using the ABI PRISM™ 7700 Sequence Detection System (PE-Applied Biosystems, Foster City, CA) according to manufacturer's instructions. This is a closed-tube, non-gel-based, fluorescence detection system which allows high-throughput quantitation of polymerase chain reaction (PCR) products in real-time. As opposed to standard PCR, in which amplification products are quantitated after the PCR is completed, products in real-time quantitative PCR are quantitated as they accumulate. This is accomplished by including in the PCR reaction an oligonucleotide probe that anneals specifically between the forward and reverse PCR primers, and contains two fluorescent dyes. A reporter dye ( e . g. , JOE or FAM, obtained from either Operon Technologies Inc., Alameda, CA or PE-Applied Biosystems, Foster City, CA) is attached to the 5' end of the probe and a quencher dye (e.g., TAMRA, obtained from either Operon Technologies Inc., Alameda, CA or PE-Applied Biosystems, Foster City, CA) is attached to the 3' end of the probe. When the probe and dyes are intact, reporter dye emission is quenched by the proximity of the 3' quencher dye. During amplification, annealing of the probe to the target sequence creates a substrate that can be cleaved by the 5 ' -exonuclease activity of Taq polymerase. During the extension phase of the PCR amplification cycle, cleavage of the probe by Taq polymerase releases the reporter dye from the remainder of the probe (and hence from the quencher moiety) and a sequence-specific fluorescent signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored at regular intervals by laser optics built into the ABI PRISM™ 7700 Sequence Detection System. In each assay, a series of parallel reactions containing serial dilutions of mRNA from untreated control samples generates a standard curve that is used to quantitate the percent inhibition after antisense oligonucleotide treatment of test samples . PCR reagents are obtained from PE-Applied Biosystems, Foster City, CA. RT-PCR reactions are carried out by adding 25 μL PCR cocktail (lx TAQMAN™ buffer A, 5.5 mM MgCl 2 , 300 μM each of dATP, dCTP and dGTP, 600 μM of dUTP, 100 nM each of forward primer, reverse primer, and probe, 20 Units RNAse inhibitor, 1.25 Units AMPLITAQ GOLD™, and 12.5 Units MuLV reverse transcriptase) to 96 well plates containing 25 μL poly (A) mRNA solution. The RT reaction is carried out by incubation for 30 minutes at 48°C. Following a 10 minute incubation at 95°C to activate the AMPLITAQ GOLD™, 40 cycles of a two-step PCR protocol are carried out: 95°C for 15 seconds (denaturation) followed by 60°C for 1.5 minutes (annealing/extension). TRAF probes and primers are designed to hybridize to the human TRAF sequence, using published sequence information. For example, GenBank Accession No. U19261, Locus name "HSU 19261" SEQ ID NO: 1; GenBank Accession No. U12597, Locus name "HSU12597" SEQ ID NO. 2; GenBank Accession No U21092, Locus name "HSU21092 SEQ ID NO: 3; GenBank Accession No. X80200, Locus name "HSMLN62" SEQ ID NO. 4; GenBank Accession No. AB000509, Locus name "AB000509 SEQ ID NO. 5; GenBank Accession No. U78798, Locus name "HSU78798" SEQ ID NO. 6. Example 14 Antisense inhibition of TRAF-1 expression- phosphorothioate oligodeoxynucleotides In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human TRAF-1 RNA, using published sequences (GenBank accession number U19261, incorporated herein as SEQ ID NO: 1). The oligonucleotides are shown in Table 1. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. U19261) , to which the oligonucleotide binds. All compounds in Table 1 are oligodeoxynucleotides with phosphorothioate backbones (internucleoside linkages) throughout. TABLE 1 Nucleotide Sequences of Human TRAF-1 Phosphorothioate Oligonucleotides SEQ TARGET GENE GENE NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET (5' -> 3') NO: COORDINATES 2 REGION 26698 TTTAAGTTGCTCCAGGGC 7 0028-0045 5 ' -UTR 26699 GCCGGGCGAGGACTGCTG 8 0093-0110 coding 26700 GCAGACGGTGGGAGGGCA 9 0139-0156 coding 26701 CTGGGCTCCTTTGGGTCC 10 0159-0176 coding 26702 CACAGCAGAGAGCCCTGG 11 0173-0190 coding 26703 ATTCCTCGGGTTCTCAGA 12 0202-0219 coding 26704 CCATTCCTCGGGTTCTCA 13 0204-0221 coding 26705 CCTCGCCATTCCTCGGGT 14 0209-0226 coding 26706 GATCCTCGCCATTCCTCG 15 0212-0229 coding 26707 AGACGGCTTCCTGGGCTT 16 0270-0287 coding 26708 TTGAAGGAGCAGCCGACA 17 0351-0368 coding 26709 GGCCTTCCACTGTTTCAT 18 0442-0459 coding 26710 CCACTTCCACGGCTGCCT 19 0527-0544 coding 26711 CGCCTGGTGACATTGGTG 20 0894-0911 coding 26712 CGCATCATACTCCCCTCT 21 1063-1080 coding 26713 AGGCGTCAATGGCGTGCT 22 1142-1159 coding 26714 GGAAGGCGTCAATGGCGT 23 1145-1162 coding 26715 GGAAGAAGAGTGGGCATC 24 1223-1240 coding 26716 CGTAGGCGTGCTTGGGTG 25 1259-1276 coding 26717 GCCCCGCCCACCCTAAGT 26 1321-1338 stop 26718 GGAGCCCCGCCCACCCTA 27 1324-1341 stop 26719 CTCAGGAGCCCCGCCCAC 28 1328-1345 3 ' -UTR 26720 AAGGGCAGGGCATCACAG 29 1380-1397 3' -UTR 26721 TTTGTGCCCTGAGGTCTT 30 1405-1422 3 ' -UTR 26722 CACCCATCTTTGTGCCCT 31 1413--1430 3 ' -UTR 26723 GGCCTCCCAGTGTCGCAT 32 1570- -1587 3 ' -UTR 26724 CCCGGTCCTGTTTCTGAC 33 1756- -1773 3 ' -UTR 26725 GCACCCCATCCCTTCCAC 34 1773- -1790 3 ' -UTR 26726 TGGAGCCGTCTGGGTTTG 35 1837- -1854 3 ' -UTR 26727 GTCTTCAAATCCAACCCC 36 1871- -1888 3 ' -UTR 26728 TTCTGGGCTGGAAGGAAA 37 1896- -1913 3 ' -UTR 26729 ACTTTCTGGGCTGGAAGG 38 1899- -1916 3 ' -UTR 26730 AGAGACTTTCTGGGCTGG 39 1903- -1920 3 ' -UTR 26731 TTTCCAGAACCCCTGTAG 40 1955- -1972 3 ' -UTR 26732 ATGTTTCCAGAACCCCTG 41 1958- -1975 3 ' -UTR 26733 GGGCTGGGTGTGCTCCTG 42 2090- -2107 3 ' -UTR 26734 TTTATGCCCCTCTTCTTC 43 2204- -2221 3 ' -UTR 26735 GGAAAGTTTATGCCCCTC 44 2210- -2227 3 ' -UTR 26736 TACGGGATTCTGGAAAGC 45 2257- -2274 3 ' -UTR 26737 AGGTGTTACGGGATTCTG 46 2263- -2280 3 ' -UTR 1 All cytidines are 5 -methyl-cytidines; all linkages are phosphorothioate linkages. 2 Coordinates from GenBank Accession No. U19261, locus name "HSU19261" SEQ ID NO.l. Example 15 : Antisense inhibition of TRAF-1 expression- phosphorothioate 2 ' -MOE gapmer oligonucleotides In accordance with the present invention, a second series of oligonucleotides targeted to human TRAF-1 were synthesized. The oligonucleotide sequences are shown in Table 2. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. U19261) , to which the oligonucleotide binds. All compounds in Table 2 are chimeric oligonucleotides ("gapmers") 18 nucleotides in length, composed of a central "gap" region consisting of ten 2 ' -deoxynucleotides, which is flanked on both sides (5' and 3' directions) by four- nucleotide "wings". The wings are composed of 2 ' - methoxyethyl (2 ' -MOE) nucleotides . The internucleoside (backbone) linkages are phosphorothioate (P=S) throughout the oligonucleotide. All cytidine residues are 5- methylcytidines . TABLE 2 Nucleotide Sequences of Human TRAF-1 Gapmer Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5' -> 3') NO: COORDINATES 2 REGION 26738 TTTAAGTTGCTCCAGGGC 7 0028-0045 5 ' -UTR 26739 GCCGGGCGAGGACTGCTG 8 0093-0110 coding 26740 GCAGACGGTGGGAGGGCA 9 0139-0156 coding 26741 CTGGGCTCCTTTGGGTCC 10 0159-0176 coding 26742 CACAGCAGAGAGCCCTGG 11 0173-0190 coding 26743 ATTCCTCGGGTTCTCAGA 12 0202-0219 coding 26744 CCATTCCTCGGGTTCTCA 13 0204-0221 coding 26745 CCTCGCCATTCCTCGGGT 14 0209-0226 coding 26746 GATCCTCGCCATTCCTCG 15 0212-0229 coding 26747 AGACGGCTTCCTGGGCTT 16 0270-0287 coding 26748 TTGAAGGAGCAGCCGACA 17 0351-0368 coding 26749 GGCCTTCCACTGTTTCAT 18 0442-0459 coding 26750 CCACTTCCACGGCTGCCT 19 0527-0544 coding 26751 CGCCTGGTGACATTGGTG 20 0894-0911 coding 26752 CGCATCATACTCCCCTCT 21 1063-1080 coding 26753 AGGCGTCAATGGCGTGCT 22 1142-1159 coding 26754 GGAAGGCGTCAATGGCGT 23 1145--1162 coding 26755 GGAAGAAGAGTGGGCATC 24 1223- -1240 coding 26756 CGTAGGCGTGCTTGGGTG 25 1259- -1276 coding 26757 GCCCCGCCCACCCTAAGT 26 1321- -1338 stop 26758 GGAGCCCCGCCCACCCTA 27 1324- -1341 stop 26759 CTCAGGAGCCCCGCCCAC 28 1328- -1345 3 ' -UTR 26760 AAGGGCAGGGCATCACAG 29 1380- -1397 3 ' -UTR 26761 TTTGTGCCCTGAGGTCTT 30 1405- -1422 3' -UTR 26762 CACCCATCTTTGTGCCCT 31 1413- -1430 3 ' -UTR 26763 GGCCTCCCAGTGTCGCAT 32 1570- -1587 3 ' -UTR 26764 CCCGGTCCTGTTTCTGAC 33 1756- -1773 3 ' -UTR 26765 GCACCCCATCCCTTCCAC 34 1773- -1790 3 ' -UTR 26766 TGGAGCCGTCTGGGTTTG 35 1837- -1854 3 ' -UTR 26767 GTCTTCAAATCCAACCCC 36 1871- -1888 3 ' -UTR 26768 TTCTGGGCTGGAAGGAAA 37 1896- -1913 3' -UTR 26769 ACTTTCTGGGCTGGAAGG 38 1899- -1916 3' -UTR 26770 AGAGACTTTCTGGGCTGG 39 1903- -1920 3 ' -UTR 26771 TTTCCAGAACCCCTGTAG 40 1955- -1972 3 '-UTR 26772 ATGTTTCCAGAACCCCTG 41 1958- -1975 3' -UTR 26773 GGGCTGGGTGTGCTCCTG 42 2090- -2107 3' -UTR 26774 TTTATGCCCCTCTTCTTC 43 2204- -2221 3 ' -UTR 26775 GGAAAGTTTATGCCCCTC 44 2210- -2227 3 ' -UTR 26776 TACGGGATTCTGGAAAGC 45 2257- -2274 3 ' -UTR 26777 AGGTGTTACGGGATTCTG 46 2263- -2280 3 ' -UTR 1 Emboldened residues are 2 ' -methoxyethoxy residues (others are 2 '-deoxy-). All 2 ' -methoxyethoxy cytidines and 2'- deoxycytidines are 5-methyl-cytidines; all linkages are phosphorothioate linkages. 2 Coordinates from GenBank Accession No. 19261, locus name "HSU19261" SEQ ID NO. 1. Example 16 : Antisense inhibition of TRAF-2 expression- phosphorothioate 2 ' -MOE gapmer oligonucleotides In accordance with the present invention, a series of oligonucleotides targeted to human TRAF-2 were synthesized. The oligonucleotide sequences are shown in Table 3. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. U12597) , to which the oligonucleotide binds. All compounds in Table 3 are chimeric oligonucleotides ("gapmers") 20 nucleotides in length, composed of a central "gap" region consisting of eight 2 ' -deoxynucleotides, which is flanked on both sides (5' and 3' directions) by six- nucleotide "wings". The wings are composed of 2 ' - methoxyethyl (2 ' -MOE) nucleotides . The internucleoside (backbone) linkages are phosphorothioate (P=S) in the central "deoxy gap" and phosphodiester (P=0) in the wings. Cytidine residues in the 2 ' -MOE wings are 5- methylcytidines . TABLE 3: Nucleotide Sequences of TRAF-2 Gapmer Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5' -> 3') NO: COORDINATES 2 REGION 16827 GoToCoGoCoAsGsCsGsCsGsCsCsGsGoAoAoToToC 47 0001-0020 5 ' -UTR 16828 CoCoAoAoCoGsGsTsCsGsCsAsGsCsGoCoGoCoCoG 48 0007-0026 5 ' -UTR 16829 CoAoGoCoCoAsTsGsAsGsAsGsCsTsGoToGoAoCoC 49 0042-0061 AUG 16830 AoCoGoCoToAsGsCsTsGsCsAsGsCsCoAoToGoAoG 50 0052-0071 AUG 16831 GoCoCoAoCoAsCsTsGsCsGsCsCsTsGoGoAoAoGoG 51 0185-0204 coding 16832 CoCoGoGoCoAsGsGsCsTsCsTsCsCsAoCoCoToCoC 52 0348-0367 coding 16833 GoCoAoGoCoGsGsCsCsTsTsCsGsTsGoGoCoAoGoC 53 0422-0441 coding 16834 CoCoToCoGoTsGsGsTsGsCsGsCsCsToToCoAoCoG 54 0576-0595 coding 16835 CoToCoGoAoCsAsCsTsTsGsCsCsAsCoAoAoGoToC 55 0675-0694 coding 16836 CoAoCoToGoCsAsCsCsTsCsGsTsGsCoToCoCoToG 56 0751-0770 coding 16837 CoCoToCoToGsCsAsGsGsAsGsCsTsCoToGoAoCoC 57 0848-0867 coding 16838 CoAoGoCoCoGsGsTsGsCsTsGsCsCsGoGoCoToGoC 58 0962-0981 coding 16839 CoCoGoGoToGsCsCsGsTsCsGsCsCsGoToToCoAoG 59 1240-1259 coding 16840 AoCoGoToCoGsGsGsCsCsTsGsAsAsGoGoCoGoToC 60 1387-1406 coding HMVEC (human dermal microvascular) cells were purchased from Clonetics (San Diego CA) and cultivated in endothelial basal medium (EBM) supplemented with 10% fetal bovine serum (HyClone, Logan UT) . Cells were grown in 100 mm petri dishes until 70-80% confluent and then treated with oligonucleotide in the presence of cationic lipid. Briefly, cells were washed with PBS and OPTI-MEM ® . OPTI- MEM ® containing 10 μg/mL LIPOFECTIN ® was added to the cells, followed by addition of oligonucleotide. The cells were incubated for 3-4 hours at 37° C, washed once with EBM/1% FBS, and allowed to recover. For determination of mRNA levels by Northern blot, total RNA was prepared from cells by the guanidinium isothiocyanate procedure or by the Qiagen RNEASY™ method (Qiagen, Valencia, CA) . Northern blot analysis was performed by standard methods (for example, Ausubel, et al . Current Protocols in Molecular Biology, Vol. 1, John Wiley and Sons, Inc., 1996, pp.4.2.1- 4.2.9) . The probe was a PCR-labeled 1-kb fragment of TRAF-2 amplified by RT-PCR according to the method of Bednarczuk et al . , Bioteαhniςrues, 1991, 10,478. RNA was quantified and normalized to G3PDH mRNA levels using a Molecular Dynamics (Sunnyvale, CA) PhosphorImager in accordance with manufacturer ' s instructions . Results are shown in Table 4. Reduction of TRAF-2 mRNA levels with oligonucleotide 16834 (SEQ ID NO. 54) was determined to be dose-dependent in the range of 1 to 100 nM. The IC 50 was approximately 10 nM. A TRAF-6 antisense oligonucleotide did not affect TRAF-2 mRNA expression. The effect of oligonucleotide 16834 (SEQ ID NO. 54) on TRAF-2 protein levels was also examined. Cells were treated with oligonucleotide and allowed to recover for 48 to 72 hours before being harvested. Protein levels were determined by western blot analysis. Dose-dependent reduction of TRAF-2 protein expression was detectable 48 hours after treatment and maximal reduction of TRAF-2 protein levels was achieved 72 hours after treatment with 100 nM oligonucleotide. TABLE 4 Activities of TRAF-2 Gapmer Oligonucleotides ISIS S SEE(Q ID GENE TARGET % mRNA % mRNA No: NO REGION EXPRESSION INHIBITION LIPOFECTIN — 100% 0% only 16827 47 5' -UTR 43% 57% 16828 48 5 ' -UTR 23% 77% 16829 49 AUG 48% 52% 16830 50 AUG 18% 82% 16831 51 coding 49% 51% 16832 52 coding 42% 58% 16833 53 coding 60% 40% 16834 54 coding 3% 97% 16835 55 coding 43% 57% 16836 56 coding 91% 9% 16837 57 coding 60% 40% 16838 58 coding 66% 34% 16839 59 coding 47% 53% 16840 60 coding 45% 55% 16841 61 coding 8% 92% 16842 62 -UTR 36% 64% 16843 63 -UTR 46% 54% 16844 64 -UTR 82% 18% 16845 65 -UTR 59% 41% 16846 66 -UTR 13% 87% 16847 67 -UTR 74% 26% 16848 68 -UTR 57% 43% ISIS 27693 (SEQ ID NO: 54) was also shown to decrease TRAF-2 mRNA levels in primary human fibroblast-like synoviocytes (obtained from surgical/biopsy specimens) . LIPOFECTIN ® was included at 3 μg/ml. A dose-response effect was obtained with an IC 50 of approximately 25 nM and nearly 90% reduction of TRAF-2 mRNA at an oligonucleotide concentration of 100 nM. Example 17 : Antisense inhibition of TRAF-3 expression- phosphorothioate oligodeoxynucleotides In accordance with the present invention, a series of oligonucleotides were designed to target human TRAF-3 RNA using published sequences (GenBank accession number HSU21092, SEQ ID NO: 3. Oligodeoxynucleotides are shown in Table 5. Target sites are indicated as nucleotide numbers on the TRAF-3 mRNA target (SEQ ID NO: 3) . TABLE 5 Nucleotide Sequences of Human TRAF-3 Phosphorothioate Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5' -> 3') NO: COORDINATES 2 REGION 26778 AGAGCCGACGACCGCCGC 71 0078-0095 5 ' -UTR 26779 GGAAGAGCCGACGACCGC 72 0081-0098 5' -UTR 26780 CGCGCCAGGAGAGTCCAT 73 0236-0253 coding 26781 TTAGCGGCGGGTTAGTCT 74 0258-0275 coding 26782 AGCTTTAGCGGCGGGTTA 75 0262-0279 coding 26783 CTCGGTCTGCTTCGGGCT 76 0401-0418 coding 26784 TGCCCACACTCGGTCTGC 77 0409-0426 coding 26785 CGGTGCCCACACTCGGTC 78 0412-0429 coding 26786 GAAGCGGTGCCCACACTC 79 0416-0433 coding 26787 TTACACGCCTTCTCCACG 80 0712-0729 coding 26788 GTATTTACACGCCTTCTC 81 0716*-0733 coding 26789 CCGGTATTTACACGCCTT 82 0719* -0736 coding 26790 GAGGGCAGGACACCACCA 83 0816* -0833 coding 26791 TGTGAGGGCAGGACACCA 84 0819* -0836 coding 26792 CACTTGTGAGGGCAGGAC 85 0823- -0840 coding 26793 GCTGGTTTGTCCCCTGAA 86 0939* -0956 coding 26794 ATCTGCTGGTTTGTCCCC 87 0943- -0960 coding 26795 CGCGGTTCTGGAGGGACT 88 1281- -1298 coding 26796 CCCCGCACTCTTGTCCAC 89 1316- -1333 coding 26797 TTGCCCCGCACTCTTGTC 90 1319- -1336 coding 26798 CCACTTGCCCCGCACTCT 91 1323- -1340 coding 26799 GAGCCACTTGCCCCGCAC 92 1326- -1343 coding 26800 TTCCGAGCCACTTGCCCC 93 1330- -1347 coding 26801 TCCGCCGCTTGTAGTCGC 94 1485- -1502 coding 26802 TGCTTCCGCCGCTTGTAG 95 1489- -1506 coding 26803 TCCTGCTTCCGCCGCTTG 96 1492- -1509 coding 26804 GTCCCCGTTCAGGTAGAC 97 1589- -1606 coding 26805 TCCCGTCCCCGTTCAGGT 98 1593- -1610 coding 26806 CCATCCCGTCCCCGTTCA 99 1596- -1613 coding 26807 TCCCCATCCCGTCCCCGT 100 1599- -1616 coding 26808 CCCTTCCCCATCCCGTCC 101 1603- -1620 coding 26809 TGCGTCCCCTTCCCCATC 102 1609- •1626 coding 26810 AAGTGCGTCCCCTTCCCC 103 1612- -1629 coding 26811 CGACAAGTGCGTCCCCTT 104 1616- -1633 coding 26812 AAGGAAGCAGGGCATCAT 105 1662- -1679 coding 26813 CTCTCCAGTGGGCTTCTT 106 1781- -1798 coding 26814 TCATCTCTCCAGTGGGCT 107 1785- -1802 coding 26815 GCTAAATCCACCTCCCCA 108 1933- -1950 3 ' -UTR 26816 TCTGCCGCTTCCTCCGTC 109 2027- -2044 3 ' -UTR 26817 CCGCCTTCTGCCGCTTCC 110 2033- • 2050 3 ' -UTR 1 All cytidines are 5 -methyl-cytidines ; all linkages are phosphorothioate linkages. 2 Coordinates from GenBank Accession NO.U21092, locus name "HSU21092" SEQ ID NO .3. Example 18 : Antisense inhibition of TRAF-3 expression- phosphorothioate 2 ' -MOE gapmer oligonucleotides In accordance with the present invention, a second series of oligonucleotides targeted to human TRAF-3 were synthesized. The oligonucleotide sequences are shown in Table 6. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. U21092) , to which the oligonucleotide binds. All compounds in Table 6 are chimeric oligonucleotides ("gapmers") 18 nucleotides in length, composed of a central "gap" region consisting of ten 2 ' -deoxynucleotides, which is flanked on both sides (5 1 and 3' directions) by four- nucleotide "wings". The wings are composed of 2 ' - methoxyethyl (2 ' -MOE) nucleotides . The internucleoside (backbone) linkages are phosphorothioate (P=S) throughout the oligonucleotide. All cytidine residues are 5- methylcytidines . TABLE 6 Nucleotide Sequences of Human TRAF-3 Gapmer Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5' -> 3') NO: COORDINATES 2 REGION 26818 AGAGCCGACGACCGCCGC 71 0078-0095 5' -UTR 26819 GGAAGAGCCGACGACCGC 72 0081-0098 5 ' -UTR 26820 CGCGCCAGGAGAGTCCAT 73 0236-0253 coding 26821 TTAGCGGCGGGTTAGTCT 74 0258-0275 coding 26822 AGCTTTAGCGGCGGGTTA 75 0262-0279 coding 26823 CTCGGTCTGCTTCGGGCT 76 0401--0418 coding 26824 TGCCCACACTCGGTCTGC 77 0409- -0426 coding 26825 CGGTGCCCACACTCGGTC 78 0412- -0429 coding 26826 GAAGCGGTGCCCACACTC 79 0416- -0433 coding 26827 TTACACGCCTTCTCCACG 80 0712- -0729 coding 26828 GTATTTACACGCCTTCTC 81 0716- -0733 coding 26829 CCGGTATTTACACGCCTT 82 0719- -0736 coding 26830 GAGGGCAGGACACCACCA 83 0816- -0833 coding 26831 TGTGAGGGCAGGACACCA 84 0819- -0836 coding 26832 CACTTGTGAGGGCAGGAC 85 0823- -0840 coding 26833 GCTGGTTTGTCCCCTGAA 86 0939- -0956 coding 26834 ATCTGCTGGTTTGTCCCC 87 0943- -0960 coding 26835 CGCGGTTCTGGAGGGACT 88 1281- -1298 coding 26836 CCCCGCACTCTTGTCCAC 89 1316- -1333 coding 26837 TTGCCCCGCACTCTTGTC 90 1319- -1336 coding 26838 CCACTTGCCCCGCACTCT 91 1323- -1340 coding 26839 GAGCCACTTGCCCCGCAC 92 1326- -1343 coding 26840 TTCCGAGCCACTTGCCCC 93 1330- -1347 coding 26841 TCCGCCGCTTGTAGTCGC 94 1485- -1502 coding 26842 TGCTTCCGCCGCTTGTAG 95 1489- -1506 coding 26843 TCCTGCTTCCGCCGCTTG 96 1492- -1509 coding 26844 GTCCCCGTTCAGGTAGAC 97 1589- -1606 coding 26845 TCCCGTCCCCGTTCAGGT 98 1593- -1610 coding 26846 CCATCCCGTCCCCGTTCA 99 1596- -1613 coding 26847 TCCCCATCCCGTCCCCGT 100 1599- -1616 coding 26848 CCCTTCCCCATCCCGTCC 101 1603- -1620 coding 26849 TGCGTCCCCTTCCCCATC 102 1609- -1626 coding 26850 AAGTGCGTCCCCTTCCCC 103 1612- -1629 coding 26851 CGACAAGTGCGTCCCCTT 104 1616- -1633 coding 26852 AAGGAAGCAGGGCATCAT 105 1662--1679 coding 26853 CTCTCCAGTGGGCTTCTT 106 1781- -1798 coding 26854 TCATCTCTCCAGTGGGCT 107 1785- -1802 coding 26855 GCTAAATCCACCTCCCCA 108 1933- -1950 3 ' -UTR 26856 TCTGCCGCTTCCTCCGTC 109 2027- -2044 3 ' -UTR 26857 CCGCCTTCTGCCGCTTCC 110 2033- -2050 3 ' -UTR 1 Emboldened residues are 2 ' -methoxyethoxy residues (others are 2 '-deoxy-). All 2 ' -methoxyethoxy cytidines and 2'- deoxycytidines are 5 -methyl -cytidines ; all linkages are phosphorothioate linkages. 2 Coordinates from GenBank Accession No. U21092, locus name "HSU21092" SEQ ID NO .3. Example 19 Antisense inhibition of TRAF-4 expression- phosphorothioate oligodeoxynucleotides In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human TRAF-4 RNA, using published sequences (GenBank accession number X80200, incorporated herein as SEQ ID NO: 4) . The oligonucleotides are shown in Table 7. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. X80200) , to which the oligonucleotide binds. All compounds in Table 7 are oligodeoxynucleotides with phosphorothioate backbones (internucleoside linkages) throughout. The compounds are analyzed for effect on TRAF mRNA levels by quantitative real-time PCR as described in other examples herein. TABLE 7 Nucleotide Sequences of Human TRAF-4 Phosphorothioate Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5' -> 3') NO: COORDINATES 2 REGION 26860 GCATGGCGGGCGAGCGGC 111 0072- -0089 AUG 26861 CCGTCGCTTGGGCTTCTC 112 0113- -0130 coding 26862 GGGCACTTGAAGACTCCT 113 0232- -0249 coding 26863 CTCAGGGCACTTGAAGAC 114 0236- -0253 coding 26864 TGGTCCTCAGGGCACTTG 115 0241- -0258 coding 26865 AAGCTGGTCCTCAGGGCA 116 0245- -0262 coding 26866 GCGGCAGCCCTCCTCACT 117 0341- -0358 coding 26867 CTCCAGCGGCAGCCCTCC 118 0346- -0363 coding 26868 TAGGGCAGGGAATGACAT 119 0411- -0428 coding 26869 CGATTAGGGCAGGGAATG 120 0415- -0432 coding 26870 GGGCAGCGATTAGGGCAG 121 0421- -0438 coding 26871 GCCTCCCCACTGAAGTCA 122 0523- -0540 coding 26872 ATGCGGGCACCACACTTA 123 0592- -0609 coding 26873 GGGCAGGCAACAGGCAGC 124 0733- -0750 coding 26874 CCACAGTGCCCACACCAC 125 0759- -0776 coding 26875 CGAGCCACAGTGCCCACA 126 0763- -0780 coding 26876 TCCTCCCGAGCCACAGTG 127 0769- -0786 coding 26877 CAGGTCCTCCCGAGCCAC 128 0773- -0790 coding 26878 GGCAGAGCACCAGGGCGG 129 0819- -0836 coding 26879 CTTTGAATGGGCAGAGCA 130 0828- -0845 coding 26880 GGAGTCTTTGAATGGGCA 131 0833- -0850 coding 26881 ATGCCGTGCCATTGCCAG 132 0875- -0892 coding 26882 CTCACCAGGGCACACATC 133 0925- -0942 coding 26883 CAGCTCCTGCCGTTGCCG 134 0944- -0961 coding 26884 ATGAGCACGCCATCACTG 135 1000- -1017 coding 26885 TGTAGCCGCCGTCCATAG 136 1033--1050 coding 26886 GCCTCCTGTAGCCGCCGT 137 1039- -1056 coding 26887 TAGAAGGCTGGGCTGAAG 138 1081- -1098 coding 26888 GTGTGTAGAAGGCTGGGC 139 1086- -1103 coding 26889 GTGTGCCCTCACCACTGC 140 1152- -1169 coding 26890 GACACGGCGGGCAAAGGG 141 1226- -1243 coding 26891 GAAGGTGACACGGCGGGC 142 1232- -1249 coding 26892 GCCCAGGGTCGCTCTGAT 143 1260- -1277 coding 26893 CTTCCAGTTTGGGTCGGG 144 1313- -1330 coding 26894 GATAACCAAAGCCCAGAG 145 1377- -1394 coding 26895 CATCGTCCTTTCCCCTCG 146 1513- -1530 3 ' -UTR 26896 GGCCAGGGCTGAAGCACC 147 1660- -1677 3 ' -UTR 26897 TTGTTTCCAGCCCTTCAT 148 1703- -1720 3 ' -UTR 26898 CATGTCTGCCCTACCCAA 149 1746- -1763 3 ' -UTR 26899 GCTCCCCTGCTGTGCCCT 150 1948- -1965 3 ' -UTR 1 All cytidines are 5-methyl-cytidines; all linkages are phosphorothioate linkages. 2 Coordinates from GenBank Accession No. X80200, locus name "HSMLN62" SEQ ID NO . 4. Example 20: Antisense inhibition of TRAF-4 expression- phosphorothioate 2 ' -MOE gapmer oligonucleotides In accordance with the present invention, a second series of oligonucleotides targeted to human TRAF-4 were synthesized. The oligonucleotide sequences are shown in Table 8. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. X80200) , to which the oligonucleotide binds. All compounds in Table 8 are chimeric oligonucleotides ("gapmers") 18 nucleotides in length, composed of a central "gap" region consisting of ten 2 ' -deoxynucleotides, which is flanked on both sides (5' and 3' directions) by four- nucleotide "wings". The wings are composed of 2 ' - methoxyethyl (2 ' -MOE) nucleotides . The internucleoside (backbone) linkages are phosphorothioate (P=S) throughout the oligonucleotide. All cytidine residues are 5- methylcytidines . Data are obtained by real-time quantitative PCR as described in other examples herein. TABLE 8 Nucleotide Sequences of Human TRAF-4 Gapmer Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5' -> 3') NO: COORDINATES 2 REGION 26900 GCATGGCGGGCGAGCGGC 111 0072-0089 AUG 26901 CCGTCGCTTGGGCTTCTC 112 0113-0130 coding 26902 GGGCACTTGAAGACTCCT 113 0232-0249 coding 26903 CTCAGGGCACTTGAAGAC 114 0236-0253 coding 26904 TGGTCCTCAGGGCACTTG 115 0241-0258 coding 26905 AAGCTGGTCCTCAGGGCA 116 0245-0262 coding 26906 GCGGCAGCCCTCCTCACT 117 0341-0358 coding 26907 CTCCAGCGGCAGCCCTCC 118 0346-0363 coding 26908 TAGGGCAGGGAATGACAT 119 0411-0428 coding 26909 CGATTAGGGCAGGGAATG 120 0415-0432 coding 26910 GGGCAGCGATTAGGGCAG 121 0421-0438 coding 26911 GCCTCCCCACTGAAGTCA 122 0523-0540 coding 26912 ATGCGGGCACCACACTTA 123 0592-0609 coding 26913 GGGCAGGCAACAGGCAGC 124 0733-0750 coding 26914 CCACAGTGCCCACACCAC 125 0759-0776 coding 26915 CGAGCCACAGTGCCCACA 126 0763-0780 coding 26916 TCCTCCCGAGCCACAGTG 127 0769--0786 coding 26917 CAGGTCCTCCCGAGCCAC 128 0773- -0790 coding 26918 GGCAGAGCACCAGGGCGG 129 0819- -0836 coding 26919 CTTTGAATGGGCAGAGCA 130 0828- -0845 coding 26920 GGAGTCTTTGAATGGGCA 131 0833- -0850 coding 26921 ATGCCGTGCCATTGCCAG 132 0875- -0892 coding 26922 CTCACCAGGGCACACATC 133 0925- -0942 coding 26923 CAGCTCCTGCCGTTGCCG 134 0944- -0961 coding 26924 ATGAGCACGCCATCACTG 135 1000- -1017 coding 26925 TGTAGCCGCCGTCCATAG 136 1033- -1050 coding 26926 GCCTCCTGTAGCCGCCGT 137 1039- -1056 coding 26927 TAGAAGGCTGGGCTGAAG 138 1081- -1098 coding 26928 GTGTGTAGAAGGCTGGGC 139 1086- -1103 coding 26929 GTGTGCCCTCACCACTGC 140 1152- -1169 coding 26930 GACACGGCGGGCAAAGGG 141 1226- -1243 coding 26931 GAAGGTGACACGGCGGGC 142 1232- -1249 coding 26932 GCCCAGGGTCGCTCTGAT 143 1260- -1277 coding 26933 CTTCCAGTTTGGGTCGGG 144 1313- -1330 coding 26934 GATAACCAAAGCCCAGAG 145 1377- -1394 coding 26935 CATCGTCCTTTCCCCTCG 146 1513- -1530 3 ' -UTR 26936 GGCCAGGGCTGAAGCACC 147 1660- -1677 3 ' -UTR 26937 TTGTTTCCAGCCCTTCAT 148 1703- -1720 3 ' -UTR 26938 CATGTCTGCCCTACCCAA 149 1746- -1763 3 ' -UTR 26939 GCTCCCCTGCTGTGCCCT 150 1948- -1965 3 ' -UTR 1 Emboldened residues are 2 ' -methoxyethoxy residues (others are 2 '-deoxy-) . All 2 ' -methoxyethoxy cytidines and 2'- deoxycytidines are 5-methyl-cytidines; all linkages are phosphorothioate linkages. 2 Coordinates from GenBank Accession No. X80200, locus name "HSMLN62" SEQ ID NO. 4. Example 21 Antisense inhibition of TRAF-5 expression- phosphorothioate oligodeoxynucleotides In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human TRAF-5 RNA, using published sequences (GenBank accession number AB000509, incorporated herein as SEQ ID NO: 5) . The oligonucleotides are shown in Table 9. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. AB000509) , to which the oligonucleotide binds. All compounds in Table 9 are oligodeoxynucleotides with phosphorothioate backbones (internucleoside linkages) throughout. TABLE 9 Nucleotide Sequences of Human TRAF-5 Phosphorothioate Oligonucleotides SEQ TARGET GENE GENE TARGET ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE REGION NO. (5- -> 3') NO: COORDINATES 2 26940 TGAATAAGCCATTGTGGG 151 0049-0066 AUG 26941 CTTTATGCTCTTCTGAAT 152 0062-0079 coding 26942 GGATGAAACCACAGGGCA 153 0083-0100 coding 26943 TCAAAGTCCAAGGAAATG 154 0120-0137 coding 26944 TGAAGCACCGAGTGGCAG 155 0195-0212 coding cn LΠ 26945 GGGCAGATTGGCACTGTG 156 0282-0299 coding 26946 CTCCTGAGATTTGATGAC 157 0313-0330 coding 26947 CTTTCCGTAGGACTGGCT 158 0491-0508 coding 26948 GATTCTGTAGATTGATGA 159 0584-0601 coding 26949 TTCATCTACCTCAGTTTT 160 0667-0684 coding 26950 TCCGTTACAGCACAGCCA 161 0735-0752 coding 26951 GCATGTGCTCCCGTAAGG 162 0788-0805 coding 26952 CTTTTCAAGTTTCTTTAT 163 0907-0924 coding 26953 CTTCCATCAAAGGTCTCA 164 1079-1096 coding cn cn Cn On σi n P OS PS OS tf PS I PS PS PS OS PS PS β β β β β β EH EH EH EH EH EH EH H EH EH H H EH -H -H -H -H -H -H ID 1=) |D ID i D ID £> ID ID TJ TJ TJ TJ Ό TJ 1 1 1 1 1 1 1 1 1 1 1 1 1 0 o o o 0 O u U Ό u u ϋ ro ro ro ro ro ro ro ro ro ro ro ro ro ro O O CN VD f- vo o in c-» CN cn H ro ro σ CN CN H rH H ro ro ro 1 VO CO ro in C o " * 00 ro in o CO rH CN ro o CN CN H rH H ro ro ro in VD f- ω cn o H CN ro in o r- co cn o H CN ro \Ω VD VD VD VO r- t-- r- t [- • r- t-- r- r- r- CO 00 00 00 H r-i H H H H H H H H H H H ΓH H rH H H H in o r- 00 cn o H CN ro in VD t~- CO cn o H CN in in in in m in vo VO VO vo vo D VD vo vo vo r- r- r- cn cn cn cn cn cn cn cn cn cn σ> cn cn σ-i cn cn cn vo vo vo o vo vo vo o o o vo vo VD o vo vo o o vo CN CN CN N CN CN CN CN CN N CN CN CN CN CN CN N N CN 26973 AGTAGGGAAGTGGCATAA 184 3295-3312 3 -UTR 26974 CATCACCAGGTAAGCAGC 185 3377-3394 3 -UTR 26975 TCCTGTTGTGAACCTATT 186 3553-3570 3 -UTR 26976 GGACTTGTGGGCTAAAGA 187 3656-3673 3 -UTR 26977 GCTCAGGAAGACAGAGTG 188 3724-3741 3 -UTR 26978 TGAACTCCTAAGCAAACC 189 3873-3890 3 -UTR 26979 GATGATGAAGGAACTCTG 190 3889-3906 3 -UTR All cytidines are 5-methyl-cytidines; all linkages are phosphorothioate linkages. Coordinates from GenBank Accession No. AB000509, locus name "AB000509" SEQ ID NO. 5 Example 22 : Antisense inhibition of TRAF-5 expression- phosphorothioate 2 ' -MOE gapmer oligonucleotides In accordance with the present invention, a second series of oligonucleotides targeted to human TRAF-5 were synthesized. The oligonucleotide sequences are shown in Table 10. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. AB000509) , to which the oligonucleotide binds. All compounds in Table 10 are chimeric oligonucleotides ("gapmers") 18 nucleotides in length, composed of a central "gap" region consisting of ten 2'- deoxynucleotides, which is flanked on both sides (5' and 3' directions) by four-nucleotide "wings". The wings are composed of 2 ' -methoxyethyl (2 ' -MOE) nucleotides . The internucleoside (backbone) linkages are phosphorothioate (P=S) throughout the oligonucleotide. All cytidine residues are 5-methylcytidines . TABLE 10 Nucleotide Sequences of Human TRAF-5 Gapmer Oligonucleotides SEQ TARGET GENE GENE TARGET REGION ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE NO. (5' -> 3') NO: COORDINATES 2 26980 TGAATAAGCCATTGTGGG 151 0049-0066 AUG 26981 CTTTATGCTCTTCTGAAT 152 0062-0079 coding 26982 GGATGAAACCACAGGGCA 153 0083-0100 coding 26983 TCAAAGTCCAAGGAAATG 154 0120-0137 coding 26984 TGAAGCACCGAGTGGCAG 155 0195-0212 coding 26985 GGGCAGATTGGCACTGTG 156 0282-0299 coding 26986 CTCCTGAGATTTGATGAC 157 0313-0330 coding 26987 CTTTCCGTAGGACTGGCT 158 0491-0508 coding 26988 GATTCTGTAGATTGATGA 159 0584-0601 coding 26989 TTCATCTACCTCAGTTTT 160 0667-0684 coding 26990 TCCGTTACAGCACAGCCA 161 0735-0752 coding 26991 GCATGTGCTCCCGTAAGG 162 0788-0805 coding 26992 CTTTTCAAGTTTCTTTAT 163 0907-0924 coding 26993 CTTCCATCAAAGGTCTCA 164 1079--1096 coding 26994 TCTAAAACGGCTAATCTT 165 1146- -1163 coding 26995 TCATCTTGTAATCTGTCA 166 1283- -1300 coding 26996 GGACTGGCTGAAGATGGA 167 1333- -1350 coding 26997 CCCTCCCTGACCCATCCC 168 1403- -1420 coding 26998 GAATGAGCCACAAAGCGG 169 1620- -1637 coding 26999 CAAGAACAGAGTGTCATC 170 1672- -1689 coding 27000 GTCTAAATCCAGGTCAAT 171 1799- -1816 3 ' -UTR 27001 AAACTTACCATCTTTCAA 172 1964- -1981 3 ' -UTR 27002 CTCTGTGTCCTCCATAAC 173 2053- -2070 3 ' -UTR 27003 CTTAACTGGAACAGCCTA 174 2167- -2184 3 ' -UTR 27004 GCAGGAAGAATGAAAATG 175 2352- -2369 3 ' -UTR 27005 TATTTGGTTGAATCTTAT 176 2501- -2518 3 ' -UTR 27006 AAATTCTATCCATCCTCA 177 2611- -2628 3 ' -UTR 27007 AAATTGTAAAGGTTTTCT 178 2683- -2700 3 ' -UTR 27008 ACAATGAAACTCTGTCTC 179 2779- -2796 3 ' -UTR 27009 GCAAAACTCCGTCTCTAC 180 2940- -2957 3 ' -UTR 27010 CAATAGTTGTCAGAGGCT 181 3055- -3072 3 ' -UTR 27011 AAGGACTCATCTCAGTTT 182 3209--3226 3 -UTR 27012 TAACAACGCAGAAGGGCT 183 3280- -3297 3 -UTR 27013 AGTAGGGAAGTGGCATAA 184 3295- -3312 3 -UTR 27014 CATCACCAGGTAAGCAGC 185 3377- -3394 3 -UTR 27015 TCCTGTTGTGAACCTATT 186 3553- -3570 3 -UTR 27016 GGACTTGTGGGCTAAAGA 187 3656- -3673 3 -UTR 27017 GCTCAGGAAGACAGAGTG 188 3724- -3741 3 -UTR 27018 TGAACTCCTAAGCAAACC 189 3873- -3890 3 -UTR 27019 GATGATGAAGGAACTCTG 190 3889- -3906 3 -UTR 1 Emboldened residues are 2 ' -methoxyethoxy residues (others are 2 '-deoxy-). All 2'- methoxyethoxy cytidines and 2 ' -deoxycytidines are 5-methyl-cytidines ; all linkages are phosphorothioate linkages. Coordinates from GenBank Accession No. AB000509, locus name "AB000509" SEQ ID NO. 5. Example 23 : Antisense inhibition of TRAF-6 expression- phosphorothioate 2 ' -MOE gapmer oligonucleotides In accordance with the present invention, a series of oligonucleotides targeted to human TRAF-6 were synthesized. The oligonucleotide sequences are shown in Table 11. Target sites are indicated by nucleotide numbers, as given in the sequence source reference (GenBank accession no. U78798) , to which the oligonucleotide binds. All compounds in Table 11 are chimeric oligonucleotides ("gapmers") 20 nucleotides in length, composed of a central "gap" region consisting of eight 2'- deoxynucleotides, which is flanked on both sides (5' and 3' directions) by six-nucleotide "wings". The wings are composed of 2 ' -methoxyethyl (2 ' -MOE) nucleotides . The internucleoside (backbone) linkages are phosphorothioate (P=S) in the "deoxy gap" and phosphodiester (P=0) in the wings. Cytidine residues in the 2 ' -MOE wings are 5- methylcytidines . TABLE 11: Nucleotide Sequences of TRAF-6 Gapmer Oligonucleotides SEQ TARGET GENE GENE ISIS NUCLEOTIDE SEQUENCE 1 ID NUCLEOTIDE TARGET NO. (5 > -> 3') NO: COORDINATES 2 REGION 15779 AoGoGoCoCoAsAsGsCsCsCsCsAsGsCoToGoCoGoG 191 0001-0020 5 ' -UTR 15880 CoGoCoCoAoCsCsTsTsCsGsCsTsGsGoCoCoGoCoC 192 0024-0043 5 ' -UTR 15881 GoAoGoAoCoGsAsGsGsCsTsGsCsTsToGoGoAoCoG 193 0071-0090 5 ' -UTR 15882 GoGoAoCoAoCsAsGsAsCsAsCsTsGsCoGoCoGoCoC 194 0091-0110 5 ' -UTR 15883 CoCoAoAoGoGsCsGsCsTsGsGsTsAsGoAoGoGoAoC 195 0111-0130 5 ' -UTR 15884 ToToGoCoToCsGsTsTsCsTsAsGsTsGoCoGoCoGoG 196 0185-0204 5 ' -UTR 15885 CoAoToAoGoTsAsAsCsTsTsGsAsTsToAoToCoAoC 197 0205-0224 AUG 15886 AoGoCoAoGoAsCsTsCsAsTsAsGsTsAoAoCoToToG 198 0213-0232 AUG 15887 AoCoAoGoToTsTsAsGsCsAsGsAsCsToCoAoToAoG 199 0220-0239 AUG 15888 AoCoAoGoCoGsCsTsAsCsAsGsGsAsGoCoToGoGoC 200 0291-0310 coding 15889 AoToToGoAoTsTsTsTsAsTsGsAsTsGoCoAoGoGoC 201 0495-0514 coding 15890 GoToGoAoCoCsTsGsCsAsTsCsCsCsToToAoToToG 202 0511-0530 coding 15891 GoToCoToCoAsGsTsTsCsCsAsTsCsToToGoToGoC 203 0641-0660 coding 15892 AoGoAoGoCoAsAsAsCsTsCsAsCsAsAoToGoToGoC 204 0678-0697 coding Cn cn σi σi σi cn σi i cn cn Cn Cn σ cn cn PS PS OS β β β β β β β β β β β β β β β EH EH E H -H •H -H -H •H •H -H • H -H -H •H •H • H •H -H ID D T3 TJ TJ TJ TJ TJ TJ T3 TJ TJ TJ TJ TJ TJ TJ 0 0 0 0 0 0 0 0 0 O 0 0 0 o 0 - - - U u U U o U J u u U u u U υ u ro ro ro ro in o o cn ro m 00 CN in ro σ rH in ro in VO o ro H r- o H ^ VD ro CO CN r- CM in cn *« * H ro cn f- CO 00 o O o o H H CM CN ^ in in r- CO oo CO σ o o H rH H H H H H H H H H H rH H • ^ vo H H O "* o cn ro VO <tf H CN VD <* vo r- H H cn in 00 O CN <tf H VD O in o ro r- CN cn H r- r- 00 cn O O o H H CN CM in in r- f- 00 00 o o o o H H H H H H H H H H H H H in VD 00 cn o H CN ro ^ in VD ι 00 cn o H CN o o o o o H H H H H H H H rH H CM CN CN CM CN CM CN CN CN CN CN CN CN CM CN CN CN CN CN CN CM < CJ CJ O CJ CD CJ CD CJ CJ U CD CJ CD CD CD < EH 0 o 0 0 0 O 0 O o o 0 0 0 O O O o O u CJ EH o EH CJ EH CJ EH EH EH CD CD CD EH CD o o 0 0 0 O 0 0 0 0 O 0 0 O O O O O CD J CD CJ CD CD CD CD H CJ EH CD CD EH CJ < CD H o 0 0 0 0 O 0 O 0 0 0 0 0 O 0 o O 0 CD CD EH EH EH H < CD J CD u CD < EH CD CD CD EH 0 o 0 0 O O o O o 0 0 0 o O 0 0 O O EH < H J CD CD CJ EH CD CD < CJ EH EH < CJ 0 o 0 0 0 O 0 O o 0 0 o 0 O 0 O O 0 J J H J CD H < u < CD EH < H CD < CD CJ CD cn cn cn cn cn n cn cn cn cn cn cn cn cn cn cn cn cn CD CD < H < < < CJ EH ϋ CD EH CD < < CJ O cn cn cn cn cn cn w cn cn cn cn cn cn cn n cn cn cn J EH CJ H EH u CD < H EH EH EH U EH CJ < EH EH cn cn cn cn cn cn n cn cn cn cn cn cn cn cn cn cn cn < < CD EH EH EH CD EH U J CD CJ En u CJ CD cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn CD CD CD O EH J < U < CD CD < EH EH CD CD EH CJ cn cn cn cn cn cn cn cn cn cn cn cn cn ω cn cn cn cn O EH H EH EH EH EH EH CJ CJ EH CD CJ EH EH J cn cn cn cn cn cn cn n cn cn cn cn cn cn cn cn cn n CD EH < CD J EH U J CD EH CJ EH ϋ CD < CD EH CJ cn cn cn cn cn cn cn cn cn cn cn cn n cn cn cn cn cn < CD < EH U EH < ϋ < < CJ EH EH EH cn cn n cn cn cn cn cn cn cn n cn cn cn cn cn cn cn < u < J U < U H CD CJ ϋ CJ CJ CJ EH CD EH cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn cn CD CJ CJ CJ EH < < < H CD CD J < CD J H H H 0 o 0 0 0 o o 0 0 O O 0 0 O 0 O O O CD CD <5 CJ H < CJ CD H H H H H < < H CJ < O 0 O 0 0 0 0 0 0 O O O O o o O 0 o EH H u CD CD CJ H u H < EH CD H < H H < H 0 O 0 0 0 0 0 O O O O O O 0 0 O 0 O H < EH H EH J J CD < < J J u CD J < 0 0 O O O 0 0 0 0 0 o 0 0 o 0 O 0 0 EH < EH CD CD CD CD CD J CD J J J CD CD EH CD CJ 0 o 0 0 0 o o 0 o 0 0 0 0 0 0 O 0 O EH < < J CD CD J < J J CJ CD CD < CD EH CD ro •φ in vo r » 00 cn o H CN ro in vo c * - 00 cn o σ* cn cn cn cn cn cn o o o o o o o o o o H 00 00 00 CO 00 CO 00 cn cn cn cn cn cn cn cn cn cn cn in in in in in in in in m in in m in in in in in m H H H H H H H H H H H H H H H H H 15911 GoGoAoAoCoGsTsGsTsGsGsAsTsTsCoCoCoAoGoG 223 1967-1986 3' -UTR 15912 ToGoCoToGoCsAsAsCsAsTsGsCsCsAoCoAoGoGoC 224 2017-2036 3' -UTR 15913 AoToAoCoAoCsCsAsGsAsGsCsAsAsAoAoGoCoCoC 225 2078-2097 3' -UTR 15914 AoAoAoAoGoAsCsTsGsAsAsCsTsTsToToAoAoGoG 226 scrambled control 23247 AoCoToToAoAsTsTsAs£sCsAsTsGsAoCoToAoGoT 227 15910 mismatch 23248 CoCoAoCoGoAsGsGsAsGsCsAs£sCsAoToCoAoAoG 228 16834 mismatch 27691 AsCsAsTsAsTsTsTsCsCsCsGsTsGsGsCsTsTsGsT 222 1871-1890 3' -UTR 27692 AoCoAoToAsTsTsTs£s£sCsGsTsGsGsCoToToGoT 222 1871-1890 3' -UTR 1 Emboldened residues are 2 ' -methoxyethoxy residues (others are 2 ' -deoxy) . All 2'- methoxyethoxy cytidines are 5-methyl-cytidines, underlined "C" are 5-methyl-cytidine; "s' linkages are phosphorothioate linkages, "o" linkages are phosphodiester linkages. 2 Coordinates from GenBank Accession No. U78798, locus name "HSU78798" SEQ ID NO. 6. HMVEC cells were grown in 100 mm petri dishes until 70-80% confluent and then treated with oligonucleotide in the presence of cationic lipid. Briefly, cells were washed with PBS and OPTI-MEM ® . OPTI-MEM ® containing 10 μg/mL LIPOFECTIN ® (Life Technologies, Rockville MD) was added to the cells, followed by addition of oligonucleotide. The cells were incubated for 3-4 hours at 37° C, washed once with EBM/1% FBS, and allowed to recover. For determination of mRNA levels by Northern blot, total RNA was prepared from cells by the guanidinium isothiocyanate procedure or by the Qiagen RNEASY™ method (Qiagen, Valencia, CA) . Northern blot analysis was performed by standard methods (for example, Ausubel, et al . Current Protocols in Molecular Biology, Vol. 1, John Wiley and Sons, Inc., 1996, pp.4.2.1-4.2.9) . The probe was a PCR-labeled 1-kb fragment of TRAF-6 amplified by RT-PCR according to the method of Bednarczuk et al . , 1991, Biotechniques 10,478. RNA was quantified and normalized to G3PDH mRNA levels using a Molecular Dynamics (Sunnyvale, CA) Phosphorlmager in accordance with manufacturer's instructions. Results are shown in Table 12. Reduction of TRAF-6 mRNA levels with oligonucleotide 15910 (SEQ ID NO. 224) was determined to be dose-dependent in the range of 1 to 100 nM. The IC 50 was approximately 2.5 nM. A TRAF-2 antisense oligonucleotide did not affect TRAF-6 mRNA expression. TABLE 12 Activities of TRAF-6 Gapmer Oligonucleotides ISIS SEQ GENE % mRNA % mRNA No: ID TARGET EXPRESSION INHIBITION NO: REGION LIPOFECTIN ® 100% 0% only 15779 191 5' -UTR 62% 38% 15880 192 5 ' -UTR 73% 27% 15881 193 5 ' -UTR 28% 72% 15882 194 5' -UTR 96% 4% 15883 195 5' -UTR 57% 43% 15884 196 5 ' -UTR 73% 27% 15885 197 AUG 61% 39% 15886 198 AUG 37% 63% 15887 199 AUG 23% 77% 15888 200 coding 31% 69% 15889 201 coding 42% 58% 15890 202 coding 49% 51% 15891 203 coding 50% 50% 15892 204 coding 32% 68% 15893 205 coding 18% 82% 15894 206 coding 43% 57% 15895 207 coding 41% 59% 15896 208 coding 20% 80% 15897 209 coding 60% 40% 15898 210 coding 23% 77% 15899 211 coding 66% 34% 15900 212 coding 54% 46% 15901 213 coding 60% 40% 15902 214 coding 76% 24% 15903 215 coding 58% 42% 15904 216 coding 77% 23% 15905 217 coding 108% 15906 218 coding 90% 10% 15907 219 coding 62% 38% 15908 220 3' -UTR 82% 18% 15909 221 3' -UTR 28% 72% 15910 222 3 ' -UTR 13% 87% 15911 223 3' -UTR 103* 15912 224 3 ' -UTR 20% 80? 15913 225 3' -UTR 97% 3% 15914 226 scrambled 70% 30? control Example 24 Effect of inhibiting TRAF Gene Expression on the Induction of E-selectin The effect of TRAF antisense oligonucleotides on the induction of E-selectin by TNFα or IL-lβ was examined. HMVEC cells were treated with either ISIS 16834 or ISIS 15910 under dose-response conditions followed by stimulation of E-selectin expression by TNFα or IL-lβ for 5 hours. The cell surface expression of E-selectin was determined by flow cytometry analysis. Dose-dependent inhibition of E-selectin cell surface induction by TNFα was observed in cells treated with the TRAF-2 antisense oligonucleotide ISIS 16834, as expected. Surprisingly, the TRAF-6 antisense compound, ISIS 15910, was able to inhibit TNFα mediated E-selectin surface expression as well, especially at higher dose. At low doses (20-50nM) , ISIS 16834 was a more effective inhibitor of TNFα-mediated E- selectin induction than ISIS 15910. Maximal inhibition of E-selectin induction for both antisense compounds was approximately 70% at 100 nM. Control oligonucleotides exhibited little to no effect on E-selectin induction. When IL-lβ was used as the stimulator, however, ISIS 15910 appeared to be a more specific and potent inhibitor of E- selectin induction than ISIS 16834, especially at relatively low doses. Example 25 Effect of TRAF Antisense Oligonucleotide on Iκb Phosphorylation and Degradation Multiple transcription factors are activated by cytokines to facilitate the induction of E-selectin. The most important and best studied transcription factors involved in the regulation of E-selectin activation include NF-KB, c-Jun and ATF-2. To clarify the roles of TRAF proteins in the activation of NF- B by cytokines, IκBα phosphorylation and degradation assays were performed with antisense oligonucleotide treated cells. Cells were treated with either ISIS 16834 or ISIS 15910 and allowed to recover for 48-72 hours. Tumor necrosis factor-α (TNF-α) or interleukin-1-β (IL-lβ) was added for 5 to 30 minutes before cells were harvested. Western blot analysis with antibody specific for phospho-IκBα was performed to study the phosphorylation of IκBα. The blots were then stripped and reblotted with antibody against IκBα to study the degradation of IκBα. IκBα was heavily phosphorylated 5 minutes after addition of either cytokine . By 30 minutes, IκBα was reduced, probably as a result of IκBα degradation. In TNFα-stimulated cells, the majority of the IκBα had been degraded after 5 minutes of stimulation. By 30 minutes, IκBα was almost completely gone. In contrast, the degradation of IκBα in IL-lβ stimulated cells was slower with the majority of IκBα degraded by 30 minutes. Neither ISIS 16834 nor ISIS 15910 affected IκBα phosphorylation and degradation induced by TNFα. ISIS 15910 has little effect on IL-lβ mediated IκBα phosphorylation and degradation either. Hyperphosphorylation of IκBα was observed in ISIS 16834 treated, IL-lβ induced cells. In summary, the antisense oligonucleotides do not inhibit the phosphorylation and degradation of IκBα. Example 26 Effect of TRAF Antisense Oligonucleotides on JNK Activities MAP kinases play central roles in the activation of specific transcription factors crucial to the induction of cell adhesion molecules. To examine the effect of TRAF antisense oligonucleotides on JNK activities, in vi tro kinase assays were performed on extracts derived from cells treated with TRAF antisense oligonucleotides. Cells were treated with TRAF-2 or TRAF-6 antisense compounds, (ISIS 16834 or ISIS 15910, respectively) allowed to recover for 48-72 hours, at which time TNF was added for 15 minutes prior to the cell lysis and the initiation of the kinase assays. Specific c-Jun conjugated agarose beads were used to precipitate JNK. ATP was added to the immunoprecipitated kinase complexes and the reaction mixes were analyzed on SDS-PAGE. Western blotting with antibodies specific for phosphorylated c-Jun was carried out to determine relative kinase activity. JNK was activated by TNFα after a 15 minute incubation, as indicated by the heavy phosphorylation of c-Jun. ISIS 16834 reduced JNK activity in TNFα-treated cells but not in IL-lβ treated cells. Some hyperphosphorylation of c-Jun induced by IL-lβ in ISIS 16834 treated cells was observed. ISIS 15910 reduced the c-Jun phosphorylation mediated by both IL-lβ and TNFα. Some inhibitory effect of ISIS 15910 on JNK activity was also observed in TNFα-induced cells. This result is consistent with the inhibitory effects of TRAF antisense oligonucleotides on the surface expression of E-selectin. Example 27 Inhibition of cell proliferation by antisense oligonucleotide targeted to TRAF-2 HeLa cells were treated with ISIS 16834 (200 nM) and counted 48 hours later. Cells were trypsinized, stained with trypan blue and counted (floating cells included) . Cell number in ISIS 16834-treated cultures was reduced by 61% compared to untreated control cultures. Example 28 Induction of apoptosis by antisense oligonucleotide targeted to TRAF-2 HeLa cells were treated with ISIS 16834 (200 nM) and the number of dead cells was measured by trypan blue exclusion 48 hours later. In cultures untreated with oligonucleotide, only 5% of cells were dead. In cultures treated with ISIS 16834, 44% of cells were dead. Example 29 Dose response of apoptosis in response to ISIS 16834 targeted to TRAF-2 HeLa cells were treated with ISIS 16834 at various doses and the number of sub-Gl apoptotic cells was counted using propidium iodide and FACS 48 hours after treatment with ISIS 16834 at 100, 200 and 300 nM. Culture supernatant and floating cells were transferred to FACS tubes. Cells were washed with PBS, trypsinized and washed in PBS, then fixed in ice-cold 70% ethanol for 12-15 hours in the freezer. Cells were centrifuged and resuspended in propidium iodide (PI) mix (50 μg/ml PI, 5 μg/ml RNAse cocktail, Cat. # 2286, Ambion, Austin TX) in the dark for 1 hour at room temperature before FACS analysis. Percent apoptotic cells after treatment at 100, 200 and 300 nM doses was approximately 29%, 46% and 58%, respectively, compared to 5% for untreated control cells. Example 30 Time course of apoptosis in response to ISIS 16834 targeted to TRAF-2 The number of sub-Gl apoptotic HeLa cells was counted 1, 2 and 3 days after treatment with ISIS 16834 at 200 nM using methods described in the previous example. Percent apoptotic cells after treatment at these time points was approximately 10%, 46% and 53%, respectively, compared to 5% after 3 days for untreated control cells. Example 31 Antisense inhibition of TRAF-3 expression The antisense oligonucleotides shown in Tables 5 and 6 were screened in T-24 cells for ability to inhibit human TRAF-3 expression. Results are shown in Tables 13 and 14, respectively. Table 13 Inhibition of TRAF-3 mRNA levels by phosphorothioate oligodeoxynucleotides ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID REGION 5'--> 3' NO. 26778 5'UTR 78 AGAGCCGACGACCGCCGC 0 71 26779 5'UTR 81 GGAAGAGCCGACGACCGC 0 72 26780 CDS 236 CGCGCCAGGAGAGTCCAT 0 73 26781 CDS 258 TTAGCGGCGGGTTAGTCT 22 74 26782 CDS 262 AGCTTTAGCGGCGGGTTA 9 75 26783 CDS 401 CTCGGTCTGCTTCGGGCT 30 76 26784 CDS 409 TGCCCACACTCGGTCTGC 67 77 26785 CDS 412 CGGTGCCCACACTCGGTC 70 78 26786 CDS 416 GAAGCGGTGCCCACACTC 66 79 26787 CDS 712 TTACACGCCTTCTCCACG 77 80 26788 CDS 716 GTATTTACACGCCTTCTC 25 81 26789 CDS 719 CCGGTATTTACACGCCTT 35 82 26790 CDS 816 GAGGGCAGGACACCACCA 81 83 26791 CDS 819 TGTGAGGGCAGGACACCA 70 84 26792 CDS 823 CACTTGTGAGGGCAGGAC 69 85 26793 CDS 939 GCTGGTTTGTCCCCTGAA 42 86 26794 CDS 943 ATCTGCTGGTTTGTCCCC 73 87 26795 CDS 1281 CGCGGTTCTGGAGGGACT 39 88 26796 CDS 1316 CCCCGCACTCTTGTCCAC 36 89 26797 CDS 1319 TTGCCCCGCACTCTTGTC 19 90 26798 CDS 1323 CCACTTGCCCCGCACTCT 70 91 26799 CDS 1326 GAGCCACTTGCCCCGCAC 53 92 26800 CDS 1330 TTCCGAGCCACTTGCCCC 22 93 26801 CDS 1485 TCCGCCGCTTGTAGTCGC 70 94 26802 CDS 1489 TGCTTCCGCCGCTTGTAG 42 95 26803 CDS 1492 TCCTGCTTCCGCCGCTTG 73 96 26804 CDS 1589 GTCCCCGTTCAGGTAGAC 43 97 26805 CDS 1593 TCCCGTCCCCGTTCAGGT 78 98 26806 CDS 1596 CCATCCCGTCCCCGTTCA 81 99 26807 CDS 1599 TCCCCATCCCGTCCCCGT 86 100 26808 CDS 1603 CCCTTCCCCATCCCGTCC 40 101 26809 CDS 1609 TGCGTCCCCTTCCCCATC 45 102 26810 CDS 1612 AAGTGCGTCCCCTTCCCC 32 103 26811 CDS 1616 CGACAAGTGCGTCCCCTT 71 104 26812 CDS 1662 AAGGAAGCAGGGCATCAT 44 105 26813 CDS 1781 CTCTCCAGTGGGCTTCTT 70 106 26814 CDS 1785 TCATCTCTCCAGTGGGCT 48 107 26815 3'UTR 1933 GCTAAATCCACCTCCCCA 0 108 26816 3 'UTR 2027 TCTGCCGCTTCCTCCGTC 41 109 26817 3'UTR 2033 CCGCCTTCTGCCGCTTCC 70 110 - ■ -Position of first nucleotide of the target site on GenBank accession number HSU21092, incorporated herein as SEQ ID NO: 3. Table 14 Inhibition of TRAF-3 mRNA levels by chimeric phosphorothioate oligonucleotides having 2 ' -MOE wings and a deoxy gap ISIS# „ T J -A Λ R Λ G Va E- c, T x SITE, 1 SEQ w UENCE %Inhib SEQ ID REGION 5 « --> 3' NO. 26818 5'UTR 78 AGAGCCGACGACCGCCGC 2 71 26819 5'UTR 81 GGAAGAGCCGACGACCGC 0 72 26820 CDS 236 CGCGCCAGGAGAGTCCAT 87 73 26821 CDS 258 TTAGCGGCGGGTTAGTCT 32 74 26822 CDS 262 AGCTTTAGCGGCGGGTTA 33 75 26823 CDS 401 CTCGGTCTGCTTCGGGCT 58 76 26824 CDS 409 TGCCCACACTCGGTCTGC 71 77 26825 CDS 412 CGGTGCCCACACTCGGTC 69 78 26826 CDS 416 GAAGCGGTGCCCACACTC 54 79 26827 CDS 712 TTACACGCCTTCTCCACG 65 80 26828 CDS 716 GTATTTACACGCCTTCTC 40 81 26829 CDS 719 CCGGTATTTACACGCCTT 77 82 26830 CDS 816 GAGGGCAGGACACCACCA 76 83 26831 CDS 819 TGTGAGGGCAGGACACCA 78 84 26832 CDS 823 CACTTGTGAGGGCAGGAC 88 85 26833 CDS 939 GCTGGTTTGTCCCCTGAA 79 86 26834 CDS 943 ATCTGCTGGTTTGTCCCC 74 87 26835 CDS 1281 CGCGGTTCTGGAGGGACT 57 88 26836 CDS 1316 CCCCGCACTCTTGTCCAC 0 89 26837 CDS 1319 TTGCCCCGCACTCTTGTC 34 90 26838 CDS 1323 CCACTTGCCCCGCACTCT 33 91 26839 CDS 1326 GAGCCACTTGCCCCGCAC 39 92 26840 CDS 1330 TTCCGAGCCACTTGCCCC 0 93 26841 CDS 1485 TCCGCCGCTTGTAGTCGC 71 94 26842 CDS 1489 TGCTTCCGCCGCTTGTAG 39 95 26843 CDS 1492 TCCTGCTTCCGCCGCTTG 47 96 26844 CDS 1589 GTCCCCGTTCAGGTAGAC 7 97 26845 CDS 1593 TCCCGTCCCCGTTCAGGT 56 98 26846 CDS 1596 CCATCCCGTCCCCGTTCA 54 99 26847 CDS 1599 TCCCCATCCCGTCCCCGT 41 100 26848 CDS 1603 CCCTTCCCCATCCCGTCC 79 101 26849 CDS 1609 TGCGTCCCCTTCCCCATC 63 102 26850 CDS 1612 AAGTGCGTCCCCTTCCCC 77 103 26851 CDS 1616 CGACAAGTGCGTCCCCTT 80 104 26852 CDS 1662 AAGGAAGCAGGGCATCAT 4 105 26853 CDS 1781 CTCTCCAGTGGGCTTCTT 64 106 26854 CDS 1785 TCATCTCTCCAGTGGGCT 55 107 26855 3'UTR 1933 GCTAAATCCACCTCCCCA 48 108 26856 3'UTR 2027 TCTGCCGCTTCCTCCGTC 39 109 26857 3'UTR 2033 CCGCCTTCTGCCGCTTCC 65 110 ■■• Position of first nucleotide of the target site on GenBank accession number HSU21092, incorporated herein as SEQ ID NO: 3. Example 32 Antisense inhibition of TRAF-4 expression The antisense oligonucleotides shown in Tables 7 and 8 were screened in T-24 cells for ability to inhibit human TRAF-4 expression. Results are shown in Tables 15 and 16, respectively. Table 15 Inhibition of TRAF-4 mRNA levels by phosphorothioate oligodeoxynucleotides ISIS# TARGET SITE 1 SEQUENCE %lnhib SEQ ID 26860 Start 72 GCATGGCGGGCGAGCGGC 111 26861 CDS 113 CCGTCGCTTGGGCTTCTC 16 112 26862 CDS 232 GGGCACTTGAAGACTCCT 0 113 26863 CDS 236 CTCAGGGCACTTGAAGAC 0 114 26864 CDS 241 TGGTCCTCAGGGCACTTG 47 115 26865 CDS 245 AAGCTGGTCCTCAGGGCA 0 116 26866 CDS 341 GCGGCAGCCCTCCTCACT 6 117 26867 CDS 346 CTCCAGCGGCAGCCCTCC 61 118 26868 CDS 411 TAGGGCAGGGAATGACAT 0 119 26869 CDS 415 CGATTAGGGCAGGGAATG 20 120 26870 CDS 421 GGGCAGCGATTAGGGCAG 54 121 26871 CDS 523 GCCTCCCCACTGAAGTCA 38 122 26872 CDS 592 ATGCGGGCACCACACTTA 56 123 26873 CDS 733 GGGCAGGCAACAGGCAGC 53 124 26874 CDS 759 CCACAGTGCCCACACCAC 34 125 26875 CDS 763 CGAGCCACAGTGCCCACA 43 126 26876 CDS 769 TCCTCCCGAGCCACAGTG 66 127 26877 CDS 773 CAGGTCCTCCCGAGCCAC 35 128 26878 CDS 819 GGCAGAGCACCAGGGCGG 54 129 26879 CDS 828 CTTTGAATGGGCAGAGCA 48 130 26880 CDS 833 GGAGTCTTTGAATGGGCA 0 131 26881 CDS 875 ATGCCGTGCCATTGCCAG 44 132 26882 CDS 925 CTCACCAGGGCACACATC 69 133 26883 CDS 944 CAGCTCCTGCCGTTGCCG 71 134 26884 CDS 1000 ATGAGCACGCCATCACTG 0 135 26885 CDS 1033 TGTAGCCGCCGTCCATAG 74 136 26886 CDS 1039 GCCTCCTGTAGCCGCCGT 53 137 26887 CDS 1081 TAGAAGGCTGGGCTGAAG 48 138 26888 CDS 1086 GTGTGTAGAAGGCTGGGC 23 139 26889 CDS 1152 GTGTGCCCTCACCACTGC 32 140 26890 CDS 1226 GACACGGCGGGCAAAGGG 52 141 26891 CDS 1232 GAAGGTGACACGGCGGGC 73 142 26892 CDS 1260 GCCCAGGGTCGCTCTGAT 80 143 26893 CDS 1313 CTTCCAGTTTGGGTCGGG 0 144 26894 CDS 1377 GATAACCAAAGCCCAGAG 45 145 26895 3'UTR 1513 CATCGTCCTTTCCCCTCG 51 146 26896 3'UTR 1660 GGCCAGGGCTGAAGCACC 53 147 26897 3'UTR 1703 TTGTTTCCAGCCCTTCAT 67 148 26898 3'UTR 1746 CATGTCTGCCCTACCCAA 0 149 26899 3'UTR 1948 GCTCCCCTGCTGTGCCCT 49 150 1 Position of first nucleotide of the target site on GenBank Accession No. X80200, locus name "HSMLN62" SEQ ID NO. 4. Table 16 Inhibition of TRAF-4 mRNA levels by chimeric phosphorothioate oligonucleotides having 2 ' -MOE wings and a deoxy gap ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26901 CDS 113 CCGTCGCTTGGGCTTCTC 25 112 26902 CDS 232 GGGCACTTGAAGACTCCT 57 113 26903 CDS 236 CTCAGGGCACTTGAAGAC 49 114 26904 CDS 241 TGGTCCTCAGGGCACTTG 115 26905 CDS 245 AAGCTGGTCCTCAGGGCA 116 26906 CDS 341 GCGGCAGCCCTCCTCACT 117 26907 CDS 346 CTCCAGCGGCAGCCCTCC 68 118 26908 CDS 411 TAGGGCAGGGAATGACAT 119 26909 CDS 415 CGATTAGGGCAGGGAATG 120 26910 CDS 421 GGGCAGCGATTAGGGCAG 39 121 26911 CDS 523 GCCTCCCCACTGAAGTCA 30 122 26912 CDS 592 ATGCGGGCACCACACTTA 44 123 26913 CDS 733 GGGCAGGCAACAGGCAGC 66 124 26914 CDS 759 CCACAGTGCCCACACCAC 43 125 26915 CDS 763 CGAGCCACAGTGCCCACA 126 26916 CDS 769 TCCTCCCGAGCCACAGTG 46 127 26917 CDS 773 CAGGTCCTCCCGAGCCAC 75 128 ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26918 CDS 819 GGCAGAGCACCAGGGCGG 74 129 26919 CDS 828 CTTTGAATGGGCAGAGCA 34 130 26920 CDS 833 GGAGTCTTTGAATGGGCA 11 131 26921 CDS 875 ATGCCGTGCCATTGCCAG 32 132 26922 CDS 925 CTCACCAGGGCACACATC 30 133 26923 CDS 944 CAGCTCCTGCCGTTGCCG 79 134 26924 CDS 1000 ATGAGCACGCCATCACTG 39 135 26925 CDS 1033 TGTAGCCGCCGTCCATAG 24 136 26926 CDS 1039 GCCTCCTGTAGCCGCCGT 61 137 26927 CDS 1081 TAGAAGGCTGGGCTGAAG 51 138 26928 CDS 1086 GTGTGTAGAAGGCTGGGC 75 139 26929 CDS 1152 GTGTGCCCTCACCACTGC 23 140 26930 CDS 1226 GACACGGCGGGCAAAGGG 27 141 26931 CDS 1232 GAAGGTGACACGGCGGGC 65 142 26932 CDS 1260 GCCCAGGGTCGCTCTGAT 76 143 26933 CDS 1313 CTTCCAGTTTGGGTCGGG 0 144 26934 CDS 1377 GATAACCAAAGCCCAGAG 0 145 26935 3*UTR 1513 CATCGTCCTTTCCCCTCG 11 146 26936 3'UTR 1660 GGCCAGGGCTGAAGCACC 79 147 26937 3'UTR 1703 TTGTTTCCAGCCCTTCAT 7 148 ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26938 3'UTR 1746 CATGTCTGCCCTACCCAA 26 149 26939 3'UTR 1948 GCTCCCCTGCTGTGCCCT 14 150 - ■ -Position of first nucleotide of the target site on GenBank Accession No. X80200, locus name "HSMLN62" SEQ ID NO . 4. Example 32 Antisense inhibition of TRAF-5 expression The antisense oligonucleotides shown in Tables 9 and 10 were screened in T-24 cells for ability to inhibit human TRAF-5 expression. Results are shown in Tables 17 and 18, respectively. Table 17 Inhibition of TRAF-5 mRNA levels by phosphorothioate oligodeoxynucleotides ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26940 Start 49 TGAATAAGCCATTGTGGG 33 151 26941 CDS 62 CTTTATGCTCTTCTGAAT 0 152 26942 CDS 83 GGATGAAACCACAGGGCA 14 153 26943 CDS 120 TCAAAGTCCAAGGAAATG 37 154 26944 CDS 195 TGAAGCACCGAGTGGCAG 37 155 26945 CDS 282 GGGCAGATTGGCACTGTG 79 156 26946 CDS 313 CTCCTGAGATTTGATGAC 0 157 26947 CDS 491 CTTTCCGTAGGACTGGCT 60 158 26948 CDS 584 GATTCTGTAGATTGATGA 2 159 26949 CDS 667 TTCATCTACCTCAGTTTT 55 160 26950 CDS 735 TCCGTTACAGCACAGCCA 59 161 26951 CDS 788 GCATGTGCTCCCGTAAGG 77 162 26952 CDS 907 CTTTTCAAGTTTCTTTAT 4 163 26953 CDS 1079 CTTCCATCAAAGGTCTCA 35 164 26954 CDS 1146 TCTAAAACGGCTAATCTT 0 165 26955 CDS 1283 TCATCTTGTAATCTGTCA 9 166 26956 CDS 1333 GGACTGGCTGAAGATGGA 7 167 26957 CDS 1403 CCCTCCCTGACCCATCCC 71 168 ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26958 CDS 1620 GAATGAGCCACAAAGCGG 68 169 26959 CDS 1672 CAAGAACAGAGTGTCATC 13 170 26960 UTR 1799 GTCTAAATCCAGGTCAAT 26 171 26961 UTR 1964 AAACTTACCATCTTTCAA 48 172 26962 UTR 2053 CTCTGTGTCCTCCATAAC 54 173 26963 UTR 2167 CTTAACTGGAACAGCCTA 35 174 26964 UTR 2352 GCAGGAAGAATGAAAATG 0 175 26965 UTR 2501 TATTTGGTTGAATCTTAT 8 176 26966 UTR 2611 AAATTCTATCCATCCTCA 32 177 26967 UTR 2683 AAATTGTAAAGGTTTTCT 22 178 26968 UTR 2779 ACAATGAAACTCTGTCTC 14 179 26969 UTR 2940 GCAAAACTCCGTCTCTAC 51 180 26970 UTR 3055 CAATAGTTGTCAGAGGCT 39 181 26971 UTR 3209 AAGGACTCATCTCAGTTT 0 182 26972 UTR 3280 TAACAACGCAGAAGGGCT 74 183 26973 UTR 3295 AGTAGGGAAGTGGCATAA 29 184 26974 UTR 3377 CATCACCAGGTAAGCAGC 60 185 26975 UTR 3553 TCCTGTTGTGAACCTATT 40 186 26976 UTR 3656 GGACTTGTGGGCTAAAGA 60 187 26977 3' UTR 3724 GCTCAGGAAGACAGAGTG 6 188 ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26978 3'UTR 3873 TGAACTCCTAAGCAAACC 23 189 26979 3'UTR 3889 GATGATGAAGGAACTCTG 20 190 ---Position of first nucleotide of the target site on GenBank GenBank Accession No. AB000509, locus name "AB000509" SEQ ID NO. 5 Table 18 Inhibition of TRAF-5 mRNA levels by chimeric phosphorothioate oligonucleotides having 2 ' -MOE wings and a deoxy gap ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26980 Start 49 TGAATAAGCCATTGTGGG 27 151 26981 CDS 62 CTTTATGCTCTTCTGAAT 43 152 26982 CDS 83 GGATGAAACCACAGGGCA 71 153 26983 CDS 120 TCAAAGTCCAAGGAAATG 48 154 26984 CDS 195 TGAAGCACCGAGTGGCAG 66 155 26985 CDS 282 GGGCAGATTGGCACTGTG 37 156 26986 CDS 313 CTCCTGAGATTTGATGAC 64 157 26987 CDS 491 CTTTCCGTAGGACTGGCT 71 158 26988 CDS 584 GATTCTGTAGATTGATGA 18 159 26989 CDS 667 TTCATCTACCTCAGTTTT 50 160 26990 CDS 735 TCCGTTACAGCACAGCCA 66 161 26991 CDS 788 GCATGTGCTCCCGTAAGG 83 162 26992 CDS 907 CTTTTCAAGTTTCTTTAT 39 163 26993 CDS 1079 CTTCCATCAAAGGTCTCA 82 164 26994 CDS 1146 TCTAAAACGGCTAATCTT 38 165 26995 CDS 1283 TCATCTTGTAATCTGTCA 61 166 26996 CDS 1333 GGACTGGCTGAAGATGGA 35 167 ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 26997 CDS 1403 CCCTCCCTGACCCATCCC 40 168 26998 CDS 1620 GAATGAGCCACAAAGCGG 76 169 26999 CDS 1672 CAAGAACAGAGTGTCATC 25 170 27000 3'UTR 1799 GTCTAAATCCAGGTCAAT 30 171 27001 UTR 1964 AAACTTACCATCTTTCAA 66 172 27002 UTR 2053 CTCTGTGTCCTCCATAAC 68 173 27003 UTR 2167 CTTAACTGGAACAGCCTA 68 174 27004 UTR 2352 GCAGGAAGAATGAAAATG 20 175 27005 UTR 2501 TATTTGGTTGAATCTTAT 38 176 27006 UTR 2611 AAATTCTATCCATCCTCA 0 177 27007 UTR 2683 AAATTGTAAAGGTTTTCT 8 178 27008 UTR 2779 ACAATGAAACTCTGTCTC 66 179 27009 UTR 2940 GCAAAACTCCGTCTCTAC 51 180 27010 UTR 3055 CAATAGTTGTCAGAGGCT 32 181 27011 UTR 3209 AAGGACTCATCTCAGTTT 20 182 27012 UTR 3280 TAACAACGCAGAAGGGCT 64 183 27013 UTR 3295 AGTAGGGAAGTGGCATAA 58 184 27014 UTR 3377 CATCACCAGGTAAGCAGC 59 185 27015 UTR 3553 TCCTGTTGTGAACCTATT 79 186 27016 3'UTR 3656 GGACTTGTGGGCTAAAGA 67 187 ISIS# TARGET SITE 1 SEQUENCE %Inhib SEQ ID 27017 3'UTR 3724 GCTCAGGAAGACAGAGTG 62 27018 3'UTR 3873 TGAACTCCTAAGCAAACC 16 189 27019 3'UTR 3889 GATGATGAAGGAACTCTG 52 190 1 Position of first nucleotide of the target site on GenBank Accession No. AB000509, locus name "AB000509" SEQ ID NO. 5. Example 33 Additional oligonucleotides targeted to TRAF-1 Additional antisense oligonucleotides targeted to TRAF-1 were designed and synthesized. All compounds are 2 ' -MOE gapmers with 2 ' -MOE nucleotides shown in bold. Backbones are phosphorothioates throughout. All C are 5-methyl C. Compounds were tested as described in Example 13 above. Compounds and results are shown in Table 19. Table 19 Antisense inhibition of TRAF-1 expression ISIS # SEQUENCE GENE START % EQ ID TARGET POS 1 INHIB NO: REGION 101869 GGACCAGCCTTGTGGAGTCC 5' UTR 5 229 101870 TCAGGGTTCCAGGCTGGCCA 5' UTR 55 230 101871 TCTCAGGGTTCCAGGCTGGC Start 57 51 231 101872 CATCTCAGGGTTCCAGGCTG Start 59 50 232 101873 GCCATCTCAGGGTTCCAGGC Start 61 5 233 101874 AGGCCATCTCAGGGTTCCAG Start 63 234 101875 GGAGGCCATCTCAGGGTTCC Start 65 235 101876 CTGGAGGCCATCTCAGGGTT Start 67 236 101877 AGCTGGAGGCCATCTCAGGG Start 69 237 ISIS # SEQUENCE GENE START % SEQ I TARGET POS 1 INHIB NO: REGION 101878 TGAGCTGGAGGCCATCTCAG Start 71 — 238 101879 CCTGAGCTGGAGGCCATCTC Start 73 28 239 101880 TGCCTGAGCTGGAGGCCATC Start 75 — 240 101881 GCTGCCTGAGCTGGAGGCCA Start 77 — 241 101882 GGGCGAGGACTGCTGCCTGA Coding 88 60 242 101883 TCTCAGAGAGACAGCCTGCA Coding 189 43 243 101884 TCCTGGGCTTATAGACTGGA Coding 260 78 244 101885 GGGCTTCCCTTGAAGGAGCA Coding 358 — 245 101886 CAACAGCAGGTTTAGGTGGG Coding 416 — 246 101887 CAGGGCCATGGGCCCAGACT Coding 479 — 247 101888 CCCGG GCAATCGACCTCC Coding 555 31 248 101889 CTCAGCCAGAAGCTTCTCCT Coding 623 53 249 101890 GGCCAGGGCCAGGTGGGAGG Coding 704 — 250 101891 TGCTGAAGCTCCACCACCCT Coding 778 11 251 101892 GTGATCTTCCACAGGAAAGT Coding 877 8 252 101893 TTGGCAGTGTAGAAGGCTGG Coding 955 27 253 101894 AAGAGCGACAGATGGGTTCT Coding 1030 61 254 101895 GCAGCATGAAGGTGACCTTG Coding 1104 — 255 101896 TCTGGAAGGACGCTGAGCTT Coding 1173 — 256 101897 CTCCACAATGCACTTGAGGA Coding 1295 35 257 101898 TGCCCTGAGGTCTTGGGTGC 3' UTR 1399 31 258 101899 ATCCTAACCAGATGGCCAGC 3' UTR 1473 70 259 101900 ACTGGCCTCCCAGTGTCGCA 3' UTR 1571 9 260 101901 GCTTGGGTCCTACGGTTCCA 3' UTR 1656 22 261 101902 TCCTGTTTCTGACCCTGGAG 3' UTR 1749 81 262 101903 CTGGGTTTGCTTGTTCACCT 3' UTR 1826 85 263 101904 CCAGGAGGCTAGAATGAGAG 3' UTR 1917 — 264 101905 TGAGGAGCTGGGAGGACAGG 3' UTR 1986 — 265 101906 TTGGGAAGCTGAGCTGCCAG 3' UTR 2066 — 266 ISIS # SEQUENCE GENE START % SEQ ID TARGET POS 1 INHIB NO : REGION 101907 ACAGTGACTGGGTTTCACCT 3' UTR 2153 35 267 101908 TTACGGGATTCTGGAAAGCA 3' UTR 2256 78 268 1 Position of first nucleotide of the target site on GenBank Accession No.U19261, locus name "HSU19261, " SEQ ID NO: 1.

Claims: What is claimed is : 1. An antisense compound 8 to 30 nucleotides in length targeted to a nucleic acid molecule encoding a human tumor necrosis factor receptor-associated factor, wherein said antisense compound inhibits the expression of human tumor necrosis factor receptor-associated factor. 2. The antisense compound of claim 1 which is an antisense oligonucleotide. 3. The antisense oligonucleotide of claim 2 which comprises at least one modified internucleoside linkage. 4. The antisense oligonucleotide of claim 3 wherein the modified internucleoside linkage is a phosphorothioate linkage . 5. The antisense oligonucleotide of claim 2 which comprises at least one modified sugar moiety. 6. The antisense oligonucleotide of claim 5 wherein the modified sugar moiety is a 2 ' -O-methoxyethyl sugar moiety. 7. The antisense oligonucleotide of claim 2 which comprises at least one modified nucleobase. 8. The antisense oligonucleotide of claim 7 wherein the modified nucleobase is a 5-methylcytosine. 9. The antisense compound of claim 2 which is a chimeric oligonucleotide. 10. The antisense compound of claim 1 wherein the human TRAF is TRAF-2 or TRAF-6. 11. A composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier or diluent. 12. The composition of claim 11 comprising a colloidal dispersion system. 13. The composition of claim 11 wherein the antisense compound is an antisense oligonucleotide. 14. A method of inhibiting the expression of tumor necrosis factor receptor-associated factor in human cells or tissues comprising contacting said cells or tissues with the antisense compound of claim 1 so that expression of tumor necrosis factor receptor-associated factor is inhibited. 15. A method of treating a human having a disease or condition associated with tumor necrosis factor receptor- associated factor comprising administering to said animal a therapeutically or prophylactically effective amount of the antisense compound of claim 1 so that expression of tumor necrosis factor receptor-associated factor is inhibited. 16. The method of claim 15 wherein the disease or condition is a hyperproliferative or inflammatory disease or condition. 17. A method of reducing jun kinase activation in cells or tissues by tumor necrosis factor-α comprising contacting said cells or tissues with an antisense compound targeted to TRAF-2. 18. A method of reducing jun kinase activation in cells or tissues comprising contacting said cells or tissues with an antisense compound targeted to TRAF-6. 19. A method of reducing E-selectin expression in cells or tissues comprising contacting said cells or tissues with an antisense compound targeted to TRAF-2 or TRAF-6.

Inventors: BAKER BRENDA F, COWSERT LEX M, MONIA BRETT P, XU XIAOXING S, BAKER, BRENDA, F., COWSERT, LEX, M., MONIA, BRETT, P., XU, XIAOXING, S.
Applicants: BAKER BRENDA F, COWSERT LEX M, ISIS PHARMACEUTICALS INC, MONIA BRETT P, XU XIAOXING S, BAKER, BRENDA, F., COWSERT, LEX, M., ISIS PHARMACEUTICALS, INC., MONIA, BRETT, P., XU, XIAOXING, S.
Application year: 1999
Main classification: C07H21
IPC codes: A61K31, A61K48, A61P29, A61P35, C12N15, C12Q1