bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human CD1D Gene Has TATA Boxless Dual Promoters: An SP1-Binding Element Determines the Function of the Proximal Promoter
Authors: Chen Qiao-Yi , Jackson Natalie 
Published: April 2014

Abstract
CD1d presents lipid Ags to a specific population of NK T cells, which are involved in the host immune defense, suppression of autoimmunity, and the rejection of tumor cells. The transcriptional control mechanism that determines the regulation and the tissue distribution of CD1d remains largely unknown. After investigating 3.7 kb 5′ upstream of the coding region, we found that human gene encoding CD1d molecule (CD1D) has TATA boxless dual promoters with multiple transcription initiation sites. The proximal promoter is located within the region of −106 to +24, and the distal promoter is located within the region of −665 to −202 with the A of the translational start codon defined as +1. The longest 5′-untranslated region derived from 5′-RACE and apparently generated by the distal promoter has 272 bp in length covering the genomic sequence of the proximal promoter. The region covering the proximal promoter gave a much higher luciferase activity in Jurkat cells than in K562 cells, whereas it was in reverse for the region covering the distal promoter, indicating a cell type sp. act. of the two promoters. Transcription factor SP1 plays a crucial role in the function of the proximal promoter. The analysis of the CD1D promoter region indicates that IFN-γ, NF-IL-6, and T cell factor 1/lymphoid enhancer-binding factor 1 are most likely involved in the regulation of CD1d expression. The illustration of the dual CD1D gene promoters will help to reveal the regulatory factors that control CD1d expression and its tissue distribution for a better understanding of the cross-regulation between CD1d and NK T cells.
Reciprocal Control of Forkhead box O 3a and c-Myc via the Phosphatidylinositol 3-Kinase Pathway Coordinately Regulates p27Kip1 Levels
Authors: Chandramohan Vidyalakshmi , Jeay Sébastien , Pianetti Stefania , Sonenshein Gail E. 
Published: April 2014

Abstract
B cell receptor (BCR) engagement of murine WEHI 231 immature B lymphoma cells leads sequentially to a drop in NF-κB and c-Myc, and induction of the p27Kip1 cyclin-dependent kinase inhibitor, which promotes growth arrest and apoptosis. BCR engagement was recently shown to induce a drop in phosphatidylinositol 3-kinase (PI3K)/Akt signaling, preceding the increase in p27. As induction of p27 is due to an increase in gene transcription, we investigated the role of the Forkhead box O (FOXO) transcription factor family, which has been shown to potently induce p27 promoter activity. We demonstrate that pharmacologic inhibitors of PI3K or BCR engagement lead to decreased inactive cytoplasmic levels and increased active functional nuclear FOXO3a. In contrast, inhibition of PI3K/Akt signaling decreased the levels of NF-κB and c-Myc, which has been shown to repress p27 promoter activity. To test the effects of ectopic c-Myc on endogenous p27 levels, WEHI 231 cells stably expressing c-Myc or empty vector DNA were prepared. Ectopic c-Myc blocked the induction of p27 expression upon either inhibition of PI3K or BCR engagement. Thus, p27Kip1 is coordinately regulated via two arms of a signaling pathway that are inversely controlled upon inhibition of PI3K: induction of the activator FOXO3a and down-regulation of the repressor c-Myc.
The Mouse Homologue of the Leukocyte-Associated Ig-Like Receptor-1 Is an Inhibitory Receptor That Recruits Src Homology Region 2-Containing Protein Tyrosine Phosphatase (SHP)-2, but Not SHP-1
Authors: Lebbink Robert Jan , de Ruiter Talitha , Verbrugge Annelies , Bril Wendy S. , Meyaard Linde 
Published: April 2014

Abstract
We report the molecular cloning and characterization of the first leukocyte-associated Ig-like receptor 1 (LAIR-1) homologue in mice that we have named mouse LAIR-1 (mLAIR-1). The mLAIR-1 gene maps to the proximal end of mouse chromosome 7 in a region syntenic with human chromosome 19q13.4 where the leukocyte receptor cluster is located. The protein shares 40% sequence identity with human LAIR-1, has a single Ig-like domain, and contains two immunoreceptor tyrosine-based inhibitory motif-like structures in its cytoplasmic tail. Mouse LAIR-1 is broadly expressed on various immune cells, and cross-linking of the molecule on stably transfected RBL-2H3 and YT.2C2 cells results in strong inhibition of their degranulation and cytotoxic activities, respectively. Upon pervanadate stimulation, the mLAIR-1 cytoplasmic tail becomes phosphorylated, thereby recruiting Src homology region 2-containing tyrosine phosphatase-2. Interestingly, unlike human LAIR-1, Src homology region 2-containing tyrosine phosphatase-1 is not recruited to the mLAIR-1 cytoplasmic tail. Screening human and mouse cell lines for mLAIR-1 and human LAIR-1 binding partners identified several lines expressing putative ligand(s) for both receptors.
Allelic Exclusion at the TCRδ Locus and Commitment to γδ Lineage: Different Modalities Apply to Distinct Human γδ Subsets
Authors: Couedel Chrystelle , Lippert Eric , Bernardeau Karine , Bonneville Marc , Davodeau François 
Published: April 2014

AbstractExpression of a β-chain, as a pre-TCR, in T cell precursors prevents further rearrangements on the alternate β allele through a strict allelic exclusion process and enables precursors to undergo differentiation. However, whether allelic exclusion applies to the TCRδ locus is unknown and the role of the γδ TCR in γδ lineage commitment is still unclear. Through the analysis of the rearrangement status of the TCRγ, δ, and β loci in human γδ T cell clones, expressing either the TCR Vδ1 or Vδ2 variable regions, we show that the rate of partial rearrangements at the δ locus is consistent with an allelic exclusion process. The overrepresentation of clones with two functional TCRγ chains indicates that a γδ TCR selection process is required for the commitment of T cell precursors to the γδ lineage. Finally, while complete TCRβ rearrangements were observed in several Vδ2 T cell clones, these were seldom found in Vδ1 cells. This suggests a competitive αβ/γδ lineage commitment in the former subset and a precommitment to the γδ lineage in the latter. We propose that these distinct behaviors are related to the developmental stage at which rearrangements occur, as suggested by the patterns of accessibility to recombination sites that characterize the Vδ1 and Vδ2 subsets.
Induction in Humans of CD8+ and CD4+ T Cell and Antibody Responses by Sequential Immunization with Malaria DNA and Recombinant Protein
Authors: Wang Ruobing , Epstein Judith , Charoenvit Yupin , Baraceros Fe Maria , Rahardjo Nancy , Gay Tanya , Banania Jo-Glenna , Chattopadhyay Rana , de la Vega Patricia , Richie Thomas L. , Tornieporth Nadia , Doolan Denise L. , Kester Kent E. , Heppner D. Gray , Norman Jon , Carucci Daniel J. , Cohen Joe D. , Hoffman Stephen L. 
Published: April 2014

Abstract
Vaccine-induced protection against diseases like malaria, AIDS, and cancer may require induction of Ag-specific CD8+ and CD4+ T cell and Ab responses in the same individual. In humans, a recombinant Plasmodium falciparum circumsporozoite protein (PfCSP) candidate vaccine, RTS,S/adjuvant system number 2A (AS02A), induces T cells and Abs, but no measurable CD8+ T cells by CTL or short-term (ex vivo) IFN-γ ELISPOT assays, and partial short-term protection. P. falciparum DNA vaccines elicit CD8+ T cells by these assays, but no protection. We report that sequential immunization with a PfCSP DNA vaccine and RTS,S/AS02A induced PfCSP-specific Abs and Th1 CD4+ T cells, and CD8+ cytotoxic and Tc1 T cells. Depending upon the immunization regime, CD4+ T cells were involved in both the induction and production phases of PfCSP-specific IFN-γ responses, whereas, CD8+ T cells were involved only in the production phase. IFN-γ mRNA up-regulation was detected in both CD45RA− (CD45RO+) and CD45RA+CD4+ and CD8+ T cell populations after stimulation with PfCSP peptides. This finding suggests CD45RA+ cells function as effector T cells. The induction in humans of the three primary Ag-specific adaptive immune responses establishes a strategy for developing immunization regimens against diseases in desperate need of vaccines.
Inhibition of 19-kDa C-Terminal Region of Merozoite Surface Protein-1-Specific Antibody Responses in Neonatal Pups by Maternally Derived 19-kDa C-Terminal Region of Merozoite Surface Protein-1-Specific Antibodies but Not Whole Parasite-Specific Antibodies
Authors: Stanisic Danielle I. , Martin Laura B. , Gatton Michelle L. , Good Michael F. 
Published: April 2014

Abstract
Immunizing pregnant women with a malaria vaccine is one approach to protecting the mother and her offspring from malaria infection. However, specific maternal Abs generated in response to vaccination and transferred to the fetus may interfere with the infant’s ability to respond to the same vaccine. Using a murine model of malaria, we examined the effect of maternal 19-kDa C-terminal region of merozoite surface protein-1 (MSP119) and Plasmodium yoelii Abs on the pups’ ability to respond to immunization with MSP119. Maternal MSP119-specific Abs but not P. yoelii-specific Abs inhibited Ab production following MSP119 immunization in 2-wk-old pups. This inhibition was correlated with the amount of maternal MSP119 Ab present in the pup at the time of immunization and was due to fewer specific B cells. Passively acquired Ab most likely inhibited the development of an Ab response by blocking access to critical B cell epitopes. If a neonate’s ability to respond to MSP119 vaccination depends on the level of maternal Abs present at the time of vaccination, it may be necessary to delay immunization until Abs specific for the vaccinating Ag have decreased.
Influenza A Vaccine Based on the Extracellular Domain of M2: Weak Protection Mediated via Antibody-Dependent NK Cell Activity
Authors: Jegerlehner Andrea , Schmitz Nicole , Storni Tazio , Bachmann Martin F. 
Published: April 2014

Abstract
Vaccination of mice with a peptide corresponding to the extracellular part of M2 protein coupled to the immunodominant domain of hepatitis B core can protect mice from a lethal challenge with influenza A virus. As the extracellular part of M2 protein is highly conserved in all known human influenza A strains, such a vaccine may protect against all human influenza A strains, which would represent a major advantage over current vaccine strategies. The present study demonstrates that protection is mediated exclusively by Abs, a very important feature of a successful preventive vaccine. However, these Abs neither bind efficiently to the free virus nor neutralize virus infection, but bind to M2 protein expressed on the surface of virus-infected cells. The presence of NK cells is important for protection, whereas complement is not, supposing that protection is mediated via Ab-dependent, cell-mediated cytotoxicity. The absence of neutralizing Abs results in much weaker protection than that achieved by vaccination with UV-inactivated influenza virus. Specifically, whereas neutralizing Abs completely eliminate signs of disease even at high viral challenge doses, M2-specific Abs cannot prevent infection, but merely reduce disease at low challenge doses. M2-specific Abs fail to protect from high challenge doses, as vaccinated mice undergo lethal infection under these conditions. In conclusion, protection mediated by M2-hepatitis B core vaccine would be insufficient during the yearly epidemics, for which full protection is desirable, and overall is clearly inferior to protection achieved by immunization with classical inactivated viral preparations.
Distinctive Roles for 2′,5′-Oligoadenylate Synthetases and Double-Stranded RNA-Dependent Protein Kinase R in the In Vivo Antiviral Effect of an Adenoviral Vector Expressing Murine IFN-β
Authors: Al-khatib Khaldun , Williams Bryan R. G. , Silverman Robert H. , Halford William , Carr Daniel J. J. 
Published: April 2014

Abstract
To evaluate the anti-HSV-1 mechanisms of murine IFN-β in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN-β (Ad:IFN-β). Ocular transduction with Ad:IFN-β resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in 1) viral titer, 2) viral gene expression, 3) IFN-γ levels, and 4) the percentage of CD8+ T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-β resulted in an elevation of the IFN-induced antiviral gene 2′,5′-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared with wild-type controls in the TG based on measurements of viral titer. However, the efficacy of Ad:IFN-β was transiently lost in the eyes of RNase L mice. By comparison, PKR-deficient mice were more susceptible to ocular HSV-1 infection, and the antiviral efficacy following transduction with Ad:IFN-β was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN, whereas the OAS pathway appears to respond to exogenous IFN, contributing to the establishment of an antiviral environment in a tissue-restricted manner.
IL-6 Prevents T Cell-Mediated Hepatitis via Inhibition of NKT Cells in CD4+ T Cell- and STAT3-Dependent Manners
Authors: Sun Rui , Tian Zhigang , Kulkarni Shalini , Gao Bin 
Published: April 2014

Abstract
The hepatoprotective effect of IL-6 on various forms of liver injury including T cell-mediated hepatitis has been well documented, and it is believed that induction of antiapoptotic proteins is an important mechanism. In this study, we provide evidence suggesting an additional mechanism involved in the protective role of IL-6 in T cell-mediated hepatitis. In NKT cell-depleted mice, Con A-induced liver injury is diminished; this can be restored by the adoptive transfer of liver mononuclear cells or NKT cells from wild-type mice, but not from IL-6-treated mice. In vitro IL-6 treatment inhibits the ability of mononuclear cells to restore Con A-induced liver injury in NKT-depleted mice, whereas the same treatment does not inhibit purified NKT cells from restoring the injury. The addition of CD3+ T cells or CD4+ T cells can restore the inhibitory effect of IL-6 on purified NKT cells, whereas the addition of CD3+ T cells from CD4-deficient mice fails to restore this inhibitory effect. The expression of IL-6R was detected in 52.6% of hepatic CD3+ T cells and 32.7% of hepatic CD4+ T cells, but only in 3.9% of hepatic NK and 1.5% of hepatic NKT cells. Finally, treatment with IL-6 induces STAT3 activation in hepatic lymphocytes and hepatic T cells, and blocking such activation abolishes the inhibitory effect of IL-6 on hepatic lymphocytes to restore liver injury. Taken together, these findings suggest that in addition to its antiapoptotic abilities, as previously well documented, IL-6/STAT3 inhibits NKT cells via targeting CD4+ T cells and consequently prevents T cell-mediated hepatitis.
Arthritogenic Properties of Double-Stranded (Viral) RNA
Authors: Zare Fariba , Bokarewa Maria , Nenonen Nancy , Bergström Thomas , Alexopoulou Lena , Flavell Richard A. , Tarkowski Andrej 
Published: April 2014

Abstract
Viral infections often lead to arthralgias and overt arthritic states. The inflammatogenic compound of the viruses giving rise to such an outcome has to date not been identified. Because expression of dsRNA is a common feature of all viruses, we decided to analyze whether this property leads to the induction of arthritis. Histological signs of arthritis were evident already on day 3 following intra-articular administration of dsRNA. Arthritis was characterized by infiltration of macrophages into synovial tissue. It was not dependent on acquired immune responses because SCID mice also raised joint inflammation. NF-κB was activated upon in vitro exposure to dsRNA, indicating its role in the induction/progression of arthritis. Importantly, we found that dsRNA arthritis was triggered through IL-1R signaling because mice being deficient for this molecule were unable to develop joint inflammation. Although dsRNA is typically recognized by Toll-like receptor 3, Toll-like receptor 3 knockout mice developed arthritis, indicating that some other receptors are instrumental in the inducing of inflammation. Our results from in vitro experiments indicate that proinflammatory cytokines and chemokines stimulating monocyte influx were readily triggered in response to stimulation with dsRNA. These findings demonstrate that viral dsRNA is clearly arthritogenic. Importantly, macrophages and their products play an important role in the development of arthritis triggered by dsRNA.
Immunopathogenesis of Experimental Ulcerative Colitis Is Mediated by Eosinophil Peroxidase
Authors: Forbes Elizabeth , Murase Tosei , Yang Ming , Matthaei Klaus I. , Lee James J. , Lee Nancy A. , Foster Paul S. , Hogan Simon P. 
Published: April 2014

Abstract
The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.
Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection
Authors: Ghanekar Anand , Mendicino Michael , Liu Hao , He Wei , Liu Mingfeng , Zhong Robert , Phillips M. James , Levy Gary A. , Grant David R. 
Published: April 2014

Abstract
Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-α in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2+/+ and fgl2+/− mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2−/− mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.
Effects of Complement C5 on Apoptosis in Experimental Autoimmune Encephalomyelitis
Authors: Niculescu Teodora , Weerth Susanna , Niculescu Florin , Cudrici Cornelia , Rus Violeta , Raine Cedric S. , Shin Moon L. , Rus Horea 
Published: April 2014

Abstract
Complement activation is involved in the initiation of Ab-mediated inflammatory demyelination in experimental autoimmune encephalomyelitis (EAE). At a sublytic dose, the C5b-9 membrane attack complex protects oligodendrocytes (OLG) from apoptosis. Using C5-deficient (C5-d) mice, we previously showed a dual role for C5: enhancement of inflammatory demyelination in acute EAE, and promotion of remyelination during recovery. In this study, we investigated the role of C5 in apoptosis in myelin-induced EAE. In acute EAE, C5-d and C5-sufficient (C5-s) mice had similar numbers of total apoptotic cells, whereas C5-s had significantly fewer than C5-d during recovery. In addition, although both groups of mice displayed TUNEL+ OLG, there were significantly fewer in C5-s than in C5-d during both acute EAE and recovery. Gene array and immunostaining of apoptosis-related genes showed that Fas ligand expression was higher in C5-s. In C5-s mice, Fas+ cells were also higher than in C5-d mice in acute EAE; however, these cells were significantly reduced during recovery. Together, these findings are consistent with the role of C5, possibly by forming the membrane attack complex, in limiting OLG apoptosis in EAE, thus promoting remyelination during recovery.
Substance P Augments Borrelia burgdorferi-Induced Prostaglandin E2 Production by Murine Microglia
Authors: Rasley Amy , Marriott Ian , Halberstadt Craig R. , Bost Kenneth L. , Anguita Juan 
Published: April 2014

Abstract
Substance P is a ubiquitous CNS neuropeptide and has recently been demonstrated to augment immune cell function during inflammatory events. Central to the ability of substance P to modulate immune cell function is the interaction of substance P with the substance P neurokinin-1 receptor expressed by a variety of immune cells, including microglia. CNS involvement during Lyme disease can occur when Borrelia burgdorferi, the causative agent of Lyme disease, gains access to the CNS. In the present study, we demonstrate that substance P augments B. burgdorferi-induced expression of mRNA encoding COX-2 and subsequent secretion of PGE2 by cultured, murine microglia. Furthermore, this effect is associated with the ability of substance P to enhance B. burgdorferi-induced NF-κB activation, as demonstrated by increased nuclear localization of the p65 (RelA) subunit of NF-κB in these cells. Interestingly, we demonstrate that substance P augments B. burgdorferi-induced expression of mRNA encoding two PGE2 receptors, E-prostanoid receptor subtypes 2 and 4, as well as each receptor protein. In addition, these effects are mediated via interactions between substance P and its high affinity receptor, as evidenced by the absence of augmented PGE2 synthesis in the presence of a specific neurokinin-1 receptor antagonist or in cells genetically deficient in the expression of these receptors. Taken together, the present demonstration that substance P can exacerbate B. burgdorferi-induced inflammatory responses in microglia in vitro may indicate a role for this neuropeptide in the development of CNS inflammation observed during human neuroborreliosis.