bluuebunny/crossref_metadata_2025_split huggingface dataset:
c-Rel Is Required for the Protection of B Cells from Antigen Receptor-Mediated, But Not Fas-Mediated, Apoptosis
Authors: Owyang Alexander M. , Tumang Joseph R. , Schram Brian R. , Hsia Constance Y. , Behrens Timothy W. , Rothstein Thomas L. , Liou Hsiou-Chi 
Published: April 2014

AbstractThe NF-κB/Rel transcription factor family has been shown to protect many cell types from apoptotic signals. However, it is not known whether NF-κB is required for all survival pathways and whether each NF-κB member plays a unique or a redundant role. Here we describe the results of studies on the role of c-Rel in survival. Mature B cells from c-Rel−/− mice exhibit defects in survival, including sensitivity to Ag receptor-mediated apoptosis as well as increased sensitivity to ionizing radiation and glucocorticoids. Transgene expression of Bcl-xL, a c-Rel target gene, rescues c-Rel−/− B cells from their survival defects. Thus, c-Rel-dependent survival pathways are crucial for protection from apoptotic signals that target the mitochondrial pathway. Despite a lack of Bcl-xL, c-Rel−/− B cells can still be rescued from Fas-mediated apoptosis via B cell receptor signaling. The Fas apoptosis inhibitor molecule and FLICE inhibitory protein (c-FLIP) proteins are up-regulated normally in c-Rel−/− B cells, and these two molecules may play a more physiological role in the Fas pathway. Furthermore, unlike the TNF sensitivity of RelA−/− fibroblasts, c-Rel-deficient fibroblasts are refractory to TNF-mediated cell death. Thus, c-Rel is dispensable for protection against death receptor-mediated apoptosis. Taken together, our data suggest that distinct NF-κB/Rel members are required for protecting cells from different types of apoptotic signals.
Characterization of Virus-Mediated Inhibition of Mixed Chimerism and Allospecific Tolerance
Authors: Williams Matthew A. , Tan Joyce T. , Adams Andrew B. , Durham Megan M. , Shirasugi Nozomu , Whitmire Jason K. , Harrington Laurie E. , Ahmed Rafi , Pearson Thomas C. , Larsen Christian P. 
Published: April 2014

AbstractSimultaneous blockade of the CD28 and CD40 T cell costimulatory pathways has been shown to effectively promote skin allograft survival in mice. Furthermore, blockade of one or both of these pathways has played a central role in the development of strategies to induce mixed hematopoietic chimerism and allospecific tolerance. It has recently been observed that the beneficial effects of CD40 blockade and donor splenocytes in prolonging skin graft survival can be abrogated by some viral infections, including lymphocytic choriomeningitis virus (LCMV). In this study, we show that LCMV infection prevents prolonged allograft survival following CD28/CD40 combined blockade. We further show that LCMV prevents the induction of allospecific tolerance and mixed hematopoietic chimerism, while delay of infection for 3–4 wk posttransplant has no effect on tolerance induction. Because of reports of anti-H-2d activity following LCMV infection, we assayed the ability of LCMV-specific T cells to respond to alloantigen at a single cell level. Although we confirm that LCMV infection induces the generation of alloreactive cells, we also demonstrate that LCMV-specific T cells do not divide in response to alloantigen. The alloresponse suppressed by costimulation blockade is restored by LCMV infection and correlates with increased dendritic cell maturation. We hypothesize that the costimulation blockade-resistant rejection mediated by LCMV could be partly attributable to the up-regulation of alternative costimulatory pathways subsequent to LCMV-induced dendritic cell maturation.
Lipopolysaccharide-Stimulated or Granulocyte-Macrophage Colony-Stimulating Factor-Stimulated Monocytes Rapidly Express Biologically Active IL-15 on Their Cell Surface Independent of New Protein Synthesis
Authors: Neely Graham G. , Robbins Stephen M. , Amankwah Ernest K. , Epelman Slava , Wong Howard , Spurrell Jason C. L. , Jandu Kiran K. , Zhu Weibin , Fogg Darin K. , Brown Christopher B. , Mody Christopher H. 
Published: April 2014

AbstractAlthough IL-15 shares many of the biological activities of IL-2, IL-2 expression is primarily under transcriptional regulation, while the mechanisms involved in the regulation of IL-15 are complex and not completely understood. In the current study, we found that CD14+ monocytes constitutively exhibit both IL-15 mRNA and protein. IL-15 protein was found stored intracellularly and stimulation of CD14+ monocytes with either LPS or GM-CSF resulted in mobilization of IL-15 stores to the plasma membrane. This rapidly induced surface expression was the result of a translocation of preformed stores, confirming that posttranslational regulatory stages limit IL-15, because it was not accompanied by an increase in IL-15 mRNA and occurred independent of de novo protein synthesis. After fixation, activated monocytes, but not resting monocytes, were found to support T cell proliferation, and this effect was abrogated by the addition of an IL-15-neutralizing Ab. The presence of preformed IL-15 stores and the ability of stimulated monocytes to mobilize these stores to their surface in an active form is a novel mechanism of regulation for IL-15.
Essential Role of Stat5 for IL-5-Dependent IgH Switch Recombination in Mouse B Cells
Authors: Horikawa Keisuke , Kaku Hiroaki , Nakajima Hiroshi , Davey Helen W. , Henninghausen Lothar , Iwamoto Itsuo , Yasue Tokutaro , Kariyone Ai , Takatsu Kiyoshi 
Published: April 2014

AbstractIL-5 stimulation of CD38-activated murine splenic B cells induces μ-γ1 CSR at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent μ-γ1 CSR. Although some of the postreceptor signaling events initiated by IL-5 in activated B cells have been characterized, the involvement of Stat in IL-5 signaling has not been thoroughly evaluated. In this study, we examined the activation of Stat5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells by IL-5. The role of Stat5a and Stat5b in IL-5-induced μ-γ1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a−/− and Stat5b−/− mice. Expression levels of CD38-induced germline γ1 transcripts and AID in Stat5a−/− and Stat5b−/− B cells upon IL-5 stimulation were comparable to those of wild-type B cells. The impaired μ-γ1 CSR by Stat5b−/− B cells, but not by Stat5a−/− B cells, was rescued in part by IL-4, as the addition of IL-4 to the culture of CD38- and IL-5-stimulated B cells induced μ-γ1 CSR leading to IgG1 production. Analysis of cell division cycle number of wild-type B cells revealed that μ-γ1 CSR was observed after five or six cell divisions. Stat5a−/− and Stat5b−/− B cells showed similar cell division cycles, but they did not undergo μ-γ1 CSR. Our data support the notion that both Stat5a and Stat5b are essential for IL-5-dependent μ-γ1 CSR and Ig secretion; however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.
Mannose Receptor Ligand-Positive Cells Express the Metalloprotease Decysin in the B Cell Follicle
Authors: Mueller Chris G. F. , Cremer Isabelle , Paulet Pierre E. , Niida Shumpei , Maeda Norihiko , Lebeque Serge , Fridman Wolf H. , Sautès-Fridman Catherine 
Published: April 2014

AbstractDecysin, a gene encoding a disintegrin metalloprotease, is transcribed in human dendritic cells (DC) and germinal centers (GC). We have cloned its murine homologue and show that it is processed by the endoprotease furin before secretion of the catalytic domain. We have defined the cell types that express decysin in mouse spleen in the course of an immune response to T cell-dependent Ags. Like in humans, decysin is transcribed by activated CD11c+ DC that enter the T cell zone from the marginal zone (MZ). In the GC, decysin is expressed by follicular DC and tingible body macrophages. In addition, a MZ cell population expresses decysin and appears to migrate into the B cell follicle. The majority of these follicle-homing cells express the mannose receptor ligand, a marker for the macrophage-like MZ metallophils. The follicle-homing cells are M-CSF dependent, as they are absent in op/op mice that lack functional M-CSF. This suggests that mannose receptor ligand+ MZ metallophils differentiate into cells that migrate from the MZ into the B cell follicle. Decysin represents the first marker for this previously unrecognized cell population of the mouse spleen, which may represent a precursor for GCDC and may be specialized in the transport of unprocessed Ag from the MZ into developing GC.
Transcriptional Suppression of Matrix Metalloproteinase-9 Gene Expression by IFN-γ and IFN-β: Critical Role of STAT-1α
Authors: Ma Zhendong , Qin Hongwei , Benveniste Etty N. 
Published: April 2014

AbstractMatrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that play crucial roles in proteolytic degradation of the extracellular matrix. Aberrant expression of the 92-kDa type IV collagenase (MMP-9) is implicated in the invasion and angiogenesis process of malignant tumors and in inflammatory diseases of the CNS. We investigated the effects of IFN-γ and IFN-β, cytokines used for treating some cancers and multiple sclerosis, on MMP-9 expression in human astroglioma and fibrosarcoma cell lines and primary astrocytes. Our results demonstrate that IFN-γ and IFN-β significantly inhibit MMP-9 enzymatic activity and protein expression that is induced by PMA and the cytokine TNF-α. The inhibitory effects of IFN-γ and IFN-β on MMP-9 expression correlate with decreased steady state MMP-9 mRNA levels and suppression of MMP-9 promoter activity. IFN-γ- and IFN-β-mediated inhibition of MMP-9 gene expression is dependent on the transcription factor STAT-1α, since IFN-γ and IFN-β fail to suppress MMP-9 expression in STAT-1α-deficient primary astrocytes and human fibrosarcoma cells. Reconstitution of human STAT-1α successfully restores the inhibitory effects of IFN-γ and IFN-β on MMP-9 gene expression. Thus, these data demonstrate the critical role of STAT-1α in IFN-γ and IFN-β suppression of MMP-9 gene expression.
Antibody Is Required for Clearance of Infectious Murine Hepatitis Virus A59 from the Central Nervous System, But Not the Liver
Authors: Matthews Amy E. , Weiss Susan R. , Shlomchik Mark J. , Hannum Lynn G. , Gombold James L. , Paterson Yvonne 
Published: April 2014

AbstractIntracerebral inoculation with mouse hepatitis virus strain A59 results in viral replication in the CNS and liver. To investigate whether B cells are important for controlling mouse hepatitis virus strain A59 infection, we infected muMT mice who lack membrane-bound IgM and therefore mature B lymphocytes. Infectious virus peaked and was cleared from the livers of muMT and wild-type mice. However, while virus was cleared from the CNS of wild-type mice, virus persisted in the CNS of muMT mice. To determine how B cells mediate viral clearance, we first assessed CD4+ T cell activation in the absence of B cells as APC. CD4+ T cells express wild-type levels of CD69 after infection in muMT mice. IFN-γ production in response to viral Ag in muMT mice was also normal during acute infection, but was decreased 31 days postinfection compared with that in wild-type mice. The role of Ab in viral clearance was also assessed. In wild-type mice plasma cells appeared in the CNS around the time that virus is cleared. The muMT mice that received A59-specific Ab had decreased virus, while mice with B cells deficient in Ab secretion did not clear virus from the CNS. Viral persistence was not detected in FcR or complement knockout mice. These data suggest that clearance of infectious mouse hepatitis virus strain A59 from the CNS requires Ab production and perhaps B cell support of T cells; however, virus is cleared from the liver without the involvement of Abs or B cells.
Hepatitis C Virus Core Protein Inhibits Human T Lymphocyte Responses by a Complement-Dependent Regulatory Pathway
Authors: Yao Zhi Qiang , Nguyen Duong Tony , Hiotellis Apostolos I. , Hahn Young S. 
Published: April 2014

Abstract
Complement proteins are involved in early innate immune responses against pathogens and play a role in clearing circulating viral Ags from the blood of infected hosts. We have previously demonstrated that hepatitis C virus (HCV) core, the first protein to be expressed and circulating in the blood of infected individuals, inhibited human T cell proliferative response through interaction with the complement receptor, globular domain of C1q receptor (gC1qR). To investigate the mechanisms of HCV core/gC1qR-induced inhibition of T cell proliferation, we examined the effect of core protein on the early events in T cell activation. We found that HCV core inhibited phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated ERK kinase (MEK). HCV core-induced impairment of ERK/MEK mitogen-activated protein kinase resulted in the inhibition of IL-2 and IL-2Rα gene transcription, which led to the inhibition of IL-2 production and high-affinity IL-2R expression. Importantly, the ability of anti-gC1qR Ab treatment to reverse HCV core-induced inhibition of ERK/MEK phosphorylation reveals that the interaction between HCV core and gC1qR is linked to the interference of ERK/MEK mitogen-activated protein kinase activation. These results imply that HCV core-induced blockage of intracellular events in T cell activation by a complement-dependent regulatory pathway may play a critical role in the establishment of HCV persistence during the acute phase of viral infection.
IL-12p40-Dependent Agonistic Effects on the Development of Protective Innate and Adaptive Immunity AgainstSalmonellaEnteritidis
Authors: Lehmann Jörg , Bellmann Steffi , Werner Christoph , Schröder Regina , Schütze Nicole , Alber Gottfried 
Published: April 2014

AbstractTo study a potential IL-12p40-dependent but IL-12p75-independent agonistic activity regulating the immune response against Salmonella Enteritidis, the course of infection in IL-12p35-deficient mice (IL-12p35−/−, capable of producing IL-12p40) was compared with that of IL-12p40−/− mice. Mice lacking IL-12p40 revealed a higher mortality rate and higher bacterial organ burden than mice capable of producing IL-12p40. This phenotype was found in both genetically susceptible (BALB/c, Itys) and resistant mice (129Sv/Ev, Ityr) indicating Ity-independent mechanisms. The more effective control of bacteria in the IL-12p35−/− mice was associated with elevated serum IFN-γ and TNF-α levels. In contrast, IL-12p40−/− mice showed reduced IFN-γ production, which was associated with significantly elevated serum IgE levels. Early during infection (days 3 and 4 postinfection), as well as late (day 20 postinfection), the number of infected phagocytes was strongly increased in the absence of IL-12p40 indicating impaired bactericidal activity when IL-12p40 was missing. Liver histopathology revealed a decreased number of mononuclear granulomas in IL-12p40−/− mice. Depletion of CD4+ or CD8+ T lymphocytes in vivo suggested that both T cell subpopulations contribute to the IL-12p40-dependent protective functions. Analysis of IL-12p40 vs IL-23p19 mRNA expression revealed an up-regulation of only IL-12p40 mRNA during Salmonella infection. Together these data indicate that IL-12p40 can induce protective mechanisms during both the innate and the adaptive type 1 immune response in Salmonella infection. This novel activity of IL-12p40 complements the well described dominant and essential role of IL-12p75 in protective immunity to Salmonella infection.
Monocyte-Fibronectin Interactions, Via α5β1 Integrin, Induce Expression of CXC Chemokine-Dependent Angiogenic Activity
Authors: White Eric S. , Livant Donna L. , Markwart Sonja , Arenberg Douglas A. 
Published: April 2014

AbstractMonocyte-derived macrophages are important sources of angiogenic factors in cancer and other disease states. Upon extravasation from vasculature, monocytes encounter the extracellular matrix. We hypothesized that interaction with extracellular matrix proteins leads monocytes to adopt an angiogenic phenotype. We performed endothelial cell chemotaxis assays on conditioned medium (CM) from monocytes that had been cultured in vitro on various matrix substrates (collagen I, laminin, Matrigel, fibronectin), in the presence of autologous serum, or on tissue culture plastic alone. Monocytes cultured on Matrigel and on fibronectin were the most potent inducers of angiogenic activity compared with tissue culture plastic or autologous serum-differentiated monocytes. This increased angiogenic activity was associated with increased expression of angiogenic CXC chemokines (IL-8, epithelial neutrophil-activating peptide-78, growth-related oncogene α, and growth-related oncogene γ) but not of vascular endothelial growth factor. Additionally, CM from monocytes cultured on fibronectin-depleted Matrigel (MGFN−) induced significantly less angiogenic activity than CM from monocytes cultured on control-depleted Matrigel. ELISA analysis of CM from monocytes cultured on MGFN− revealed a significant decrease in GRO-α and GRO-γ compared with CM from monocytes cultured on MG. Incubation of monocytes before adherence on fibronectin with PHSCN (a competitive peptide inhibitor of the PHSRN sequence of fibronectin binding via α5β1 integrin) results in diminished expression of angiogenic activity and CXC chemokines compared with control peptide. These data suggest that fibronectin, via α5β1 integrin, promotes CXC chemokine-dependent angiogenic activity from monocytes.
Chemokines Regulate IL-6 and IL-8 Production by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis
Authors: Nanki Toshihiro , Nagasaka Kenji , Hayashida Kenji , Saita Yuji , Miyasaka Nobuyuki 
Published: April 2014

AbstractRheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce inflammatory cytokines and chemokines. The expressed chemokines are thought to be involved in the migration of inflammatory cells into the synovium. In this study we show that CCL2/monocyte chemotactic protein-1, CCL5/RANTES, and CXCL12/stromal cell-derived factor-1 enhanced IL-6 and IL-8 production by fibroblast-like synoviocytes (FLS) from patients with RA, and their corresponding receptors, CCR2, CCR5, and CXCR4, respectively, were expressed by RA FLS. The chemokines stimulated RA FLS more effectively than skin fibroblasts. Culture with CCL2 enhanced phosphorylation of extracellular signal-related kinase 1 (ERK1) and ERK2, but not phosphorylation of p38 or Src. Moreover, activation of ERK1/2 was inhibited by pertussis toxin, a Gi-coupled protein inhibitor, and RS-504393, CCR2 antagonist, suggesting that ERK1/2 was activated by CCL2 via CCR2 and Gi-coupled protein. On the other hand, CCL2, CCL5, and CXCL12 were expressed on RA FLS, and their production was regulated by TNF-α, IL-1β, and TGF-β1. Our results indicate that the chemokines not only play a role in inflammatory cell migration, but are also involved in the activation of FLS in RA synovium, possibly in an autocrine or paracrine manner.
Antigen Processing Defects in Cervical Carcinomas Limit the Presentation of a CTL Epitope from Human Papillomavirus 16 E6
Authors: Evans Mererid , Borysiewicz Leszek K. , Evans Alan S. , Rowe Martin , Jones Matthew , Gileadi Uzi , Cerundolo Vincenzo , Man Stephen 
Published: April 2014

AbstractHuman papillomavirus (HPV) infection, particularly type 16, is causally associated with the development of cervical cancer. The E6 and E7 proteins of HPV are constitutively expressed in cervical carcinoma cells making them attractive targets for CTL-based immunotherapy. However, few studies have addressed whether cervical carcinomas can process and present HPV E6/E7-derived Ags for recognition by CTL. We generated HLA-A*0201-restricted CTL clones against HPV16 E629–38 that recognized HPV16 E6 Ags transfected into B lymphoblastoid cells. These CTL were unable to recognize HLA-A*0201+ HPV16 E6+ cervical carcinoma cell lines even when the level of endogenous HPV16 E6 in these cells was increased by transfection. This defect in presentation of HPV16 E629–38 correlated with low level expression of HLA class I, proteasome subunits low molecular mass protein 2 and 7, and the transporter proteins TAP1 and TAP2 in the cervical carcinoma cell lines. The expression of all of these proteins could be up-regulated by IFN-γ, but this was insufficient for CTL recognition unless the level of HPV16 E6 Ag was also increased by transfection. CTL recognition of the HPV16 E629–38 epitope in 721.174 B cells was dependent on TAP expression but independent of immunoproteasome expression. Collectively, these findings suggest that presentation of the HPV16 E629–38 epitope in cervical carcinoma cell lines is limited both by the level of TAP expression and by the low level or availability of the source HPV E6 oncoprotein. These observations place constraints on the use of this, and potentially other, HPV-derived CTL epitopes for the immunotherapy of cervical cancer.
Highly Activated CD8+ T Cells in the Brain Correlate with Early Central Nervous System Dysfunction in Simian Immunodeficiency Virus Infection
Authors: Marcondes Maria Cecilia Garibaldi , Burudi E. M. E. , Huitron-Resendiz Salvador , Sanchez-Alavez Manuel , Watry Debbie , Zandonatti Michelle , Henriksen Steven J. , Fox Howard S. 
Published: April 2014

Abstract
One of the consequences of HIV infection is damage to the CNS. To characterize the virologic, immunologic, and functional factors involved in HIV-induced CNS disease, we analyzed the viral loads and T cell infiltrates in the brains of SIV-infected rhesus monkeys whose CNS function (sensory evoked potential) was impaired. Following infection, CNS evoked potentials were abnormal, indicating early CNS disease. Upon autopsy at 11 wk post-SIV inoculation, the brains of infected animals contained over 5-fold more CD8+ T cells than did uninfected controls. In both infected and uninfected groups, these CD8+ T cells presented distinct levels of activation markers (CD11a and CD95) at different sites: brain &gt; CSF &gt; spleen = blood &gt; lymph nodes. The CD8+ cells obtained from the brains of infected monkeys expressed mRNA for cytolytic and proinflammatory molecules, such as granzymes A and B, perforin, and IFN-γ. Therefore, the neurological dysfunctions correlated with increased numbers of CD8+ T cells of an activated phenotype in the brain, suggesting that virus-host interactions contributed to the related CNS functional defects.
Dual Role of the IL-12/IFN-γ Axis in the Development of Autoimmune Myocarditis: Induction by IL-12 and Protection by IFN-γ
Authors: Eriksson Urs , Kurrer Michael O. , Sebald Wolfgang , Brombacher Frank , Kopf Manfred 
Published: April 2014

AbstractIL-12 and IFN-γ positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. We investigated the role of the IL-12/IFN-γ (Th1) axis in the development of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12, autospecific CD4+ T cells proliferated poorly and showed increased Th2 cytokine responses. However, IFN-γ-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-γ and IL-4. In conclusion, our results suggest that the IL-12/IFN-γ axis is a double-edged sword for the development of autoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-γ production from these cells limits disease progression.