bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of heat shock protein 72 synthesis by endogenous tumor necrosis factor via enhancement of the heat shock element‐binding activity of heat shock factor 1
Authors: Watanabe Naoki , Tsuji Naoki , Akiyama Shinichiro , Sasaki Hiroyoshi , Okamoto Tetsuro , Kobayashi Daisuke , Sato Tsutomu , Hagino Tsukasa , Yamauchi Naofumi , Niitsu Yoshiro , Nakai Akira , Nagata Kazuhiro 
Published: March 2007

AbstractEndogenous tumor necrosis factor (enTNF) acts as a resistance factor against cytotoxicity caused by heat by inducing manganous superoxide dismutase (MnSOD), thereby scavenging reactive oxygen free radicals. On the other hand, it is also well known that heat shock proteins (HSP) which are induced by heat stress behave as cytoprotective factor against this stress. However, the relationship of these two resistance factors is not elucidated yet. In the present study, we therefore proposed the possibility that enTNF enhances HSP72 expression. Heat‐sensitive L‐M (mouse tumorigenic fibroblast) cells, which normally do not express enTNF, were transfected with a nonsecretory‐type human TNF‐α expression vector to produce enTNF. Stable transfectants showed resistance to heat treatment and an increase of HSP72 expression. Conversely, when HeLa (human uterine cervical cancer) cells, which normally produce an appreciable amount of enTNF, were transfected with an antisense TNF‐α mRNA expression vector to inhibit enTNF synthesis, their heat sensitivity was enhanced and HSP72 expression was reduced by half. Although enTNF caused no difference in the level of heat shock factor (HSF) 1 in these cells, enTNF expression correlated well with the binding activity of HSF‐1 to a 32P‐labeled synthetic oligonucleotide containing the human heat shock element (HSE). These results indicate that enTNF participates not only in intrinsic resistance against heat via induction of MnSOD but also via enhancement of the HSE‐binding activity of HSF 1 followed by augmentation of HSP72 expression.
Analysis of susceptibility of NOD mice to spontaneous and experimentally induced thyroiditis
Authors: Damotte Diane , Colomb Evelyne , Cailleau Catherine , Brousse Nicole , Charreire Jeannine , Carnaud Claude 
Published: March 2007

AbstractBeside diabetes, non‐obese diabetic (NOD) mice develop sporadic lymphoid infiltration of the thyroid gland, mimicking Hashimoto's thyroiditis. We have examined the prevalence of those manifestations in NOD mice, the influence of the major histocompatibility complex (MHC) and the association with autoantibodies. The incidence at 1 year is of 14.3% in wild‐type NOD mice versus 19.6% in congenic NOD.H2k mice. The moderate, but statistically significant difference, based on the analysis of 161 NOD and 169 NOD.H2k mice, suggests that MHC genes partially control spontaneous NOD thyroiditis. Autoantibodies against thyroglobulin (Tg) are mouse specific and their presence correlates closely with thyroiditis. The strong correlation between cellular and humoral anomalies therefore resembles Hashimoto's thyroiditis. NOD and NOD.H2k mice actively immunized against Tg develop severe chronic lesions with epithelium necrosis and interstitial tissue fibrosis. Most interestingly, those lesions do not regress spontaneously as in CBA/J mice. Paradoxically, the response to Tg of lymph node cells from NOD mice is weaker both in proliferation and cytokine production. The defect is most evident for interferon‐γ‐producing T cells and is reflected in the marked deficit in IgG2a antibodies. Thus a moderate anti‐Tg response seems to favor chronicity of thyroiditis. In conclusion, NOD and NOD.H2k mice offer a unique opportunity of analyzing the factors leading to immune chronicity in a genetic context which promotes autoimmune endocrinopathies.
In vivo evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis
Authors: Küsters Sabine , Tiegs Gisa , Alexopoulou Lena , Pasparakis Manolis , Douni Eleni , Künstle Gerald , Bluethmann Horst , Wendel Albrecht , Pfizenmaier Klaus , Kollias George , Grell Matthias 
Published: March 2007

AbstractThe significance of tumor necrosis factor receptor 1 (TNFR1) for TNF function in vivo is well documented, whereas the role of TNFR2 so far remains obscure. In a model of concanavalin A (Con A)‐induced, CD4+ T cell‐dependent experimental hepatitis in mice, in which TNF is a central mediator of apoptotic and necrotic liver damage, we now provide evidence for an essential in vivo function of TNFR2 in this pathophysiological process. We demonstrate that a cooperation of TNFR1 and TNFR2 is required for hepatotoxicity as mice deficient of either receptor were resistant against Con A. A significant role of TNFR2 for Con A‐induced hepatitis is also shown by the enhanced sensitivity of transgenic mice overexpressing the human TNFR2. The ligand for cytotoxic signaling via both TNF receptors is the precursor of soluble TNF, i.e. transmembrane TNF. Indeed, transmembrane TNF is sufficient to mediate hepatic damage, as transgenic mice deficient in wild‐type soluble TNF but expressing a mutated nonsecretable form of TNF developed inflammatory liver disease.
Interleukin‐15 preferentially promotes the growth of intestinal intraepithelial lymphocytes bearing γδ T cell receptor in mice
Authors: Inagaki‐Ohara Kyoko , Nishimura Hitoshi , Mitani Akio , Yoshikai Yasunobu 
Published: March 2007

AbstractSeveral cytokines including stem cell factor (SCF) and interleukin (IL)‐7 are known to be required for development of γδ T cell receptor (TCR) intestinal intraepithelial lymphocytes (i‐IEL) in mice. We show here the effects of IL‐15 on the proliferation and maintenance of murine γδ i‐IEL in vitro. γδ i‐IEL constitutively expressed a high level of IL‐15 receptor α mRNA and proliferated in response to IL‐15 more vigorously than αβ i‐IEL. Vγ/δ repertoire analysis revealed that IL‐15, like IL‐2, induced polyclonal expansion of γδ i‐IEL, whereas γδ i‐IEL responding to IL‐7 showed a Vγ/δ repertoire skewed towards Vγ1/Vδ4, Vδ5. IL‐15 efficiently prevented γδ i‐IEL from apoptosis induced by growth factor deprivation. This rescue was accompanied by up‐regulation of Bcl‐2 expression. These results suggest that IL‐15 plays important roles in proliferation and maintenance of γδ i‐IEL.
The CC chemokine antagonist Met‐RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3
Authors: Elsner Jörn , Petering Holger , Höchstetter Renate , Kimmig Daniela , Wells Timothy N. C. , Kapp Alexander , Proudfoot Amanda E. J. 
Published: March 2007

AbstractEosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by chemokines. Thus, agents that would be able to inhibit or antagonize chemokine‐induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a chemokine receptor antagonist, Met‐RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)‐3 and eotaxin. Met‐RANTES was able to inhibit dose‐dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP‐3 and eotaxin. Whereas maximal and half‐maximal inhibitory effect of Met‐RANTES following stimulation with RANTES and MCP‐3 were observed at 2 μg/ml and 1 μg/ml, respectively, maximal and half‐maximal inhibitory effects of Met‐RANTES in response to eotaxin were detected at 10 μg/ml and 3 μg/ml. Moreover, eotaxin‐induced [Ca2+]i transients were only half reduced at a Met‐RANTES concentration at which RANTES and MCP‐3 were completely blocked. Besides its effect on [Ca2+]i transients, Met‐RANTES dose‐dependently inhibited actin polymerization in eosinophils following chemokine stimulation. Whereas Met‐RANTES totally inhibited RANTES‐ and MCP‐3‐induced actin polymerization at 5 μg/ml, the eotaxin‐induced response was only reduced by 50%. However, Met‐RANTES inhibited dose‐dependently the release of reactive oxygen species in response to RANTES, MCP‐3 and eotaxin. Again, eotaxin‐induced release of reactive oxygen species, however, was only half reduced at a Met‐RANTES concentration (10 μg/ml) at which RANTES and MCP‐3 were completely blocked. The results of this study show that (1) Met‐RANTES is an effective and powerful antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP‐3 and eotaxin; (2) Met‐RANTES seems to be able to antagonize the response of eosinophils through chemokine receptor 1 (CCR1) preferentially to CCR3; (3) Met‐RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.
Relapsing and remitting experimental allergic encephalomyelitis: A focused response to the encephalitogenic peptide rather than epitope spread
Authors: Takács Katalin , Chandler Phillip , Altmann Daniel M. 
Published: March 2007

AbstractThe progression of experimental allergic encephalomyelitis (EAE) in certain mouse strains has been reported to involve a broadening of the response to myelin antigens, apparently resulting from priming to endogenous determinants of the myelin sheath. The phenomenon has been termed determinant spread. Interest in this effect has centered on the mechanism it offers to explain the progressive, relapsing and remitting course of EAE and indeed of multiple sclerosis. We have conducted a systematic, longitudinal study in SJL mice to look for determinant spread during relapsing and remitting EAE, correlating epitope recognition and cytokine production with disease severity. Disease was induced using three of the four encephalitogenic proteolipid protein or myelin basic protein epitopes, and responses to each of four epitopes recognized by SJL T cells were tracked through acute disease, remission and relapse. The responses of lymph node cells, splenocytes and central nervous system (CNS)‐infiltrating T cells were analyzed. While marginal, transient responses to secondary epitopes were detectable in splenocytes, CNS‐infiltrating cells showed a dominant response to the original disease‐inducing epitope without evidence of a shift to other determinants during relapse. Disease relapse was correlated with an increase in CNS‐infiltrating cells and a high proliferative and interferon (IFN)‐γ response to the disease‐inducing peptide. During remission, there was a decrease in numbers of cells infiltrating the CNS. These cells were down‐regulated, showing low if any response to the myelin peptides tested as measured by proliferation, production of IFN‐γ or production of IL‐4. Our findings argue strongly against a causal role for determinant spread in disease relapse as observed in these models of EAE.
Interactions between membrane IgM and the cytoskeleton involve the cytoplasmic domain of the immunoglobulin receptor
Authors: Park Jun Young , Jongstra‐Bilen Jenny 
Published: March 2007

AbstractCross‐linking induced interactions between the membrane form of immunoglobulin (mIg) and the cytoskeletal matrix have been described by several groups. To date, the function of mIgM association with the cytoskeleton is not yet understood. Delineation of the molecular basis of these interactions will be instrumental in elucidating their function. We have previously shown that the Igα/β heterodimer is not required for ligand‐induced mIgM binding to the cytoskeleton. In this study, we have investigated the role of other B cell‐specific proteins in mediating these interactions. For this, we expressed mIgM in the non‐hematopoietic human cervical carcinoma cell line HeLa S3 and verified the capacity of the surface‐expressed IgM to interact with the cytoskeletal matrix upon cross‐linking with anti‐μ chain antibodies. We show here that only the mIgM molecule itself and no other B cell‐specific protein(s) is required in mediating mIgM interactions with actin filaments. In an attempt to determine the cytoskeleton‐binding site of mIgM we investigated the role of the cytoplasmic tail of mIgM (KVK) in binding the receptor to actin‐based microfilaments. Using mutated forms of mIgM expressed in J558L cells, we show here that KVK plays a role in mediating these interactions. The absence of KVK did not, however, completely abrogate mIgM‐cytoskeletal interactions, suggesting that there are additional molecular requirements for the ligand‐induced mIgM binding to the cytoskeletal matrix.
Thiol modulation inhibits the interleukin (IL)‐1‐mediated activation of an IL‐1 receptor‐associated protein kinase and NF‐xB
Authors: Tewes Frank , Böl Gaby‐Fleur , Brigelius‐Flohé Regina 
Published: March 2007

AbstractThe interleukin‐1 receptor type I (IL‐1RI) is associated with other proteins thus forming a complex system by which IL‐1 exerts its various signals. The initiating event is still uncertain, but activation of a recently described receptor‐associated protein kinase is one of the earliest events detectable (Martin et al., Eur. J. Immunol. 1994. 24: 1566). IL‐1 signaling is commonly accompanied by oxidative processes and is thought to be subject to redox regulation. We therefore investigated whether the activation of the IL‐1RI‐associated protein kinase could be a target for redox regulation and whether an altered activity of the kinase could influence IL‐1‐mediated NF‐xB activation. A murine T cell line, EL4, was stimulated with IL‐1 with and without pretreatment with different compounds known to influence the cellular redox status. Thiol modifying agents like diamide, menadione, pyrrolidine dithiocarbamate (PDTC), diethyl dithiocarbamate or phenylarsine oxide inhibited the IL‐1‐induced activation of the IL‐1RI‐associated protein kinase. N‐Acetylcysteine, α,α′‐dipyridyl, aminotriazole or nitrofurantoin did not show any effect. The inhibition by PDTC was reversible unless glutathione synthesis was blocked by buthionine sulfoximine. The described conditions which inhibited or prevented the activation of the IL‐1RI‐associated kinase similarly impaired the activation of NF‐xB in EL4 cells. From these observations we conclude that free thiols in the IL‐1RI complex are essential for the activation of the IL‐1RI‐associated protein kinase and that this process is mandatory for IL‐1 signaling leading to NF‐xB activation.
Sequence analysis of rat integrin αE1 and αE2 subunits: Tissue expression reveals phenotypic similarities between intraepithelial lymphocytes and dendritic cells in lymph
Authors: Brenan Mary , Rees D. Jasper G. 
Published: March 2007

AbstractThe integrin αOX‐62 subunit is defined by the OX‐62 monoclonal antibody that was raised against rat dendritic cells in lymph (veiled cells) and shows properties similar to those of human αE2 that is predominantly expressed on intraepithelial lymphocytes. To clone αOX‐62, rat probes generated using primers specific for the human αE sequence were used to screen rat T cell cDNA libraries. cDNA clones encoding two similar but not identical α subunits that are closely related to but distinct from human αE were isolated. αE1 is predicted to be the rat homolog of mouse αM290 and αE2 corresponds to rat αOX‐62. Immunofluorescence analysis revealed that mouse αE1 and rat αE2 are expressed in dendritic epidermal T cells in the skin, intraepithelial lymphocytes in the small intestine and in cells with a dendritic morphology present at sites where γδ T cells occur in lymphoid organs. Unexpectedly, αE2 is co‐expressed with intracellular CD3‐δ and a 33‐kDa CD3 chain but not the T cell receptor in veiled cells. These findings suggest that veiled cells may be derived from a lymphoid precursor. Furthermore, veiled cells show phenotypic similarities to intraepithelial lymphocytes.
The 5′ hypermutation boundary of x chains is independent of local and neighbouring sequences and related to the distance from the initiation of transcription
Authors: Rada Cristina , Yélamos José , Dean Wendy , Milstein César 
Published: March 2007

AbstractThe hypermutation of antibody genes targets 1–2 kb of DNA which includes the rearranged V(D)J gene segments. The precise nature, location and limits of the targeted region are of considerable interest in terms of the mechanism of hypermutation. We have analyzed the frequency and distribution of mutations in the 5′ region of immunoglobulins using several modified x transgenes. We found that the position of the boundary, relative to the transcription initiation site, is not affected by the sequence of the V segment or by substituting the x chain promoter for a β‐globin promoter. Furthermore, the deletion of the leader intron (containing the hypermutation boundary) does not affect hypermutation per se, but shifts the boundary from the leader intron to the V region such that the distance between the boundary and the site of initiation of transcription remains constant. These results show that the position of the hypermutation boundary (about 185 bases downstream of the site of initiation of transcription) is not defined by the nucleotide sequence but rather by the distance to a fixed upstream position. Although mutations are also observed in the region upstream of the boundary, the frequency at which they occur is one order of magnitude lower relative to the frequency observed in the V segment. Nonetheless this upstream mutation rate remains more than two orders of magnitude higher than that of somatic genes. We discuss possible mechanisms explaining the nature and position of the boundary in the context of an error‐prone DNA repair model.
CD40 ligand inhibits Fas/CD95‐mediated apoptosis of human blood‐derived dendritic cells
Authors: Koppi Thelma A. , Tough‐Bement Teresa , Lewinsohn David M. , Lynch David H. , Alderson Mark R. 
Published: March 2007

AbstractDendritic cells (DC) are considered to be the most potent antigen‐presenting cells (APC) in the immune system. In this study, we analyzed the regulation of apoptosis of human peripheral blood‐derived DC. DC were generated from adherent peripheral blood mononuclear cells that had been cultured for 7 days with granulocyte‐macrophage colony‐stimulating factor and interleukin‐4. These cells displayed phenotypic properties of DC, including dendritic processes, expression of CD1a and lack of expression of CD14, and were very potent at presenting soluble antigens to T cells. Blood‐derived DC were demonstrated to express the Fas/CD95 antigen and an agonist antibody to CD95 strongly induced apoptotic cell death in these cells. Soluble trimeric CD40 ligand potently inhibited both CD95‐mediated and spontaneous apoptosis in DC. The data suggest that interactions between members of the tumor necrosis factor family of ligands expressed by T cells with their receptors on DC play an important role in the regulation of apoptosis in DC during antigen presentation and may, therefore, regulate the duration of T cell expansion and cytokine production.
High sensitivity of transgenic mice expressing soluble TNFR1 fusion protein to mycobacterial infections: Synergistic action of TNF and IFN‐γ in the differentiation of protective granulomas
Authors: Garcia Irène , Miyazaki Yoshitaka , Marchal Gilles , Lesslauer Werner , Vassalli Pierre 
Published: March 2007

AbstractTo investigate the role of tumor necrosis factor (TNF) in protective immune responses to Mycobacterium tuberculosis and M. bovis Bacillus Calmette Guérin (BCG), we have used transgenic mice unable to use TNF because of the expression of high amounts of a soluble TNF receptor (R) type I (sTNFR1) fusion protein, and studied resistance of these mice to infection by lethality assays, evaluation of bacterial recovery and histologic examination. These mice showed a strongly increased sensitivity to M. tuberculosis and BCG infections, with bacterial overgrowth and marked inhibition of macrophage differentiation within granulomas; after M. tuberculosis infection, this resulted in extensive lesions of caseous necrosis in the lung. To explore the respective roles of TNF and interferon (IFN)‐γ in resistance to BCG and granuloma differentiation, controls and sTNFR1‐transgenic mice were compared to IFN‐γR mutant mice and mice double defective in TNF and IFN‐γ activity (obtained by crossing transgenic and mutant mice). The three groups of deficient mice showed a strongly enhanced susceptibility to BCG infection, with the following decreasing order of sensitivity between groups: TNF + IFN‐γ → TNF → IFN‐γ‐deficient mice. The hepatic granulomas of IFN‐γR mutant mice were small and contained eosinophils but few differentiated macrophages; compared to those of sTNFR1‐transgenic mice, acid‐fast bacilli were less numerous within the macrophages. Granulomas of double‐deficient mice were strikingly different by their very large size and cellular content, made up large numbers of polymorphonuclears, eosinophils, and cells undergoing apoptosis, but without detectable differentiated macrophages; acid‐fast bacilli were spread in the lesions. These studies show the essential role of both TNF and IFN‐γ in the development, during mycobacterial infections, of protective granulomas containing highly differentiated macrophages capable of destroying ingested bacteria, and emphasize that these two cytokines act synergistically in granuloma formation.
IgE secretion is attenuated by an inhibitor of proteolytic processing of CD23 (FcεRII)
Authors: Christie Gary , Barton Aisling , Bolognese Brian , Buckle Derek R. , Cook Richard M. , Hansbury Michael J. , Harper Gregory P. , Marshall Lisa A. , McCord Mark E. , Moulder Kevin , Murdock Paul R. , Seal Sheila M. , Spackman Vivienne M. , Weston Beverley J. , Mayer Ruth J. 
Published: March 2007

AbstractCD23, the low‐affinity IgE receptor, is up‐regulated on interleukin (IL)‐4‐stimulated B cells and monocytes, with a concomitant increase in the release of soluble fragments of CD23 (sCD23) into the medium by proteolytic processing of the surface‐bound intact CD23. The effect of inhibition of the processing of CD23 on IgE production in human and mouse cells and in a mouse model in vivo was evaluated. CD23 processing to sCD23 from RPMI 8866 (a human Epstein‐Barr virus‐transformed B cell line) cell membranes was inhibited by a broad‐spectrum matrix‐metalloprotease inhibitor, batimastat, with an IC50 of 0.15 μM. Batimastat also inhibited CD23 processing in whole RPMI 8866 cells as well as in IL‐4‐stimulated purified human monocytes with similar IC50. Batimastat inhibited IgE production from IL‐4/anti‐CD40‐stimulated human tonsil B cells as well as mouse splenic B cells in a manner consistent with inhibition of CD23 processing. Release of soluble fragments of CD23 in the cell supernatants of tonsil B cells was inhibited over the concentration range of 1–10 μM batimastat and intact cell surface CD23 was increased on mouse splenic B cells in the presence of these concentrations of batimastat. IgE production of IL‐4‐stimulated human peripheral blood mononuclear cells was also blocked by 1–10 μM batimastat, again with comparable inhibition of sCD23 release over the same concentration range. Finally, in a mouse model of IgE production, batimastat inhibited IgE production in response to ovalbumin challenge as determined by serum IgE levels. Taken together, the data support a role of CD23 in IgE production and point to CD23 processing to sCD23 as a therapeutically relevant control point in the regulation of IgE synthesis.