bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jak2 Dampens the Induction by IL-1β of Prostaglandin Endoperoxide H Synthase 2 Expression in Human Orbital Fibroblasts: Evidence for Divergent Influence on the Prostaglandin E2 Biosynthetic Pathway
Authors: Han Rui , Chen Beiling , Smith Terry J. 
Published: April 2014

Abstract
Prostaglandin endoperoxide H synthase 2 (PGHS-2) catalyzes the rate-limiting steps in the synthesis of PGE2. It is substantially but transiently induced in human orbital fibroblasts treated with IL-1β. In this study, we report that the induction of PGHS-2 by IL-1β is dramatically enhanced and prolonged when Jak2 signaling is abrogated, either with the specific inhibitor AG490 or by transiently transfecting fibroblasts with a dominant negative mutant Jak2. Attenuating Jak2 increases PGHS-2 steady-state mRNA levels, a consequence of increased gene transcription and mRNA survival in IL-1β-treated cultures. Surprisingly, interrupting Jak2 function also blocked the expected increase in PGE2 synthesis usually provoked by IL-1β. This resulted from the rapid loss of IL-1β-dependent arachidonate release and by attenuation of group IIA secreted PLA2 (sPLA2) gene induction. Supplying Jak2-compromised cultures with exogenous arachidonate failed to increase PGE2 production in response to IL-1β until cells were mechanically disrupted. However, transiently transfecting them with wild-type sPLA2 fully restored prostanoid production to anticipated levels. sPLA2 expression following transfection resulted in increased IL-1β-dependent PGHS-2 and microsomal PGE2 synthase levels. Thus, sPLA2 plays important roles in PGE2 synthesis in addition to its release of arachidonate. Our findings suggest that Jak2 ordinarily dampens and limits the duration of the PGHS-2 induction by IL-1β. Moreover, it is required for IL-1β-dependent signaling to sPLA2, the expression and activity of which are necessary for up-regulating PGE2 synthesis in orbital fibroblasts.
Elevated Urinary VCAM-1, P-Selectin, Soluble TNF Receptor-1, and CXC Chemokine Ligand 16 in Multiple Murine Lupus Strains and Human Lupus Nephritis
Authors: Wu Tianfu , Xie Chun , Wang Hong W. , Zhou Xin J. , Schwartz Noa , Calixto Sergio , Mackay Meggan , Aranow Cynthia , Putterman Chaim , Mohan Chandra 
Published: April 2014

Abstract
In an effort to identify potential biomarkers in lupus nephritis, urine from mice with spontaneous lupus nephritis was screened for the presence of VCAM-1, P-selectin, TNFR-1, and CXCL16, four molecules that had previously been shown to be elevated in experimental immune nephritis, particularly at the peak of disease. Interestingly, all four molecules were elevated ∼2- to 4-fold in the urine of several strains of mice with spontaneous lupus nephritis, including the MRL/lpr, NZM2410, and B6.Sle1.lpr strains, correlating well with proteinuria. VCAM-1, P-selectin, TNFR-1, and CXCL16 were enriched in the urine compared with the serum particularly in active disease, and were shown to be expressed within the diseased kidneys. Finally, all four molecules were also elevated in the urine of patients with lupus nephritis, correlating well with urine protein levels and systemic lupus erythematosus disease activity index scores. In particular, urinary VCAM-1 and CXCL16 showed superior specificity and sensitivity in distinguishing subjects with active renal disease from the other systemic lupus erythematosus patients. These studies uncover VCAM-1, P-selectin, TNFR-1, and CXCL16 as a quartet of molecules that may have potential diagnostic significance in lupus nephritis. Longitudinal studies are warranted to establish the clinical use of these potential biomarkers.
Cutting Edge: A Transcriptional Repressor and Corepressor Induced by the STAT3-Regulated Anti-Inflammatory Signaling Pathway
Authors: El Kasmi Karim C. , Smith Amber M. , Williams Lynn , Neale Geoffrey , Panopolous Athanasia , Watowich Stephanie S. , Häcker Hans , Foxwell Brian M. J. , Murray Peter J. 
Published: April 2014

Abstract
IL-10 regulates anti-inflammatory signaling via the activation of STAT3, which in turn controls the induction of a gene expression program whose products execute inhibitory effects on proinflammatory mediator production. In this study we show that IL-10 induces the expression of an ETS family transcriptional repressor, ETV3, and a helicase family corepressor, Strawberry notch homologue 2 (SBNO2), in mouse and human macrophages. IL-10-mediated induction of ETV3 and SBNO2 expression was dependent upon both STAT3 and a stimulus through the TLR pathway. We also observed that ETV3 expression was strongly induced by the STAT3 pathway regulated by IL-10 but not by STAT3 signaling activated by IL-6, which cannot activate the anti-inflammatory signaling pathway. ETV3 and SBNO2 repressed NF-κB- but not IFN regulatory factor 7 (IRF7)-activated transcriptional reporters. Collectively our data suggest that ETV3 and SBNO2 are components of the pathways that contribute to the downstream anti-inflammatory effects of IL-10.
Cutting Edge: Tissue-Resident Memory CTL Down-Regulate Cytolytic Molecule Expression following Virus Clearance
Authors: Mintern Justine D. , Guillonneau Carole , Carbone Francis R. , Doherty Peter C. , Turner Stephen J. 
Published: April 2014

Abstract
CTL express lytic proteins that mediate the cytolysis of virus-infected cells. In this study, cytolytic transcriptional profiles were determined for individual CTL responding to influenza A virus and HSV-1. During acute infection, influenza-specific CTL in the spleen and respiratory airways displayed highly activated cytolytic profiles, as did HSV-1-specific CTL localized in the spleen, skin, and dorsal root ganglia (DRG). In contrast, memory CTL dramatically down-regulated cytolytic molecule transcription. This occurred for both lymphoid (spleen) and tissue-resident (skin and/or lung) memory CTL. In contrast, HSV-1-specific CTL localized in the dorsal root ganglia in the presence latent HSV-1 Ag did not down-regulate cytolytic molecule transcription. Therefore, both lymphoid and tissue-resident memory CTL down-regulate cytolytic molecule transcription following virus clearance unless localized Ag is present.
Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins
Authors: Binder Robert J. , Kelly John B. , Vatner Ralph E. , Srivastava Pramod K. 
Published: April 2014

Abstract
The peptide-binding property of MHC is central to adaptive immunological functions. A similar property of heat shock proteins (HSPs) hsp70 and hsp90 has been implicated in Ag presentation by MHC and in cross-priming. The peptide-binding pocket of hsp70 has been characterized structurally and functionally and a peptide-binding site in gp96 (of hsp90 family) has been defined. Nonetheless, questions persist whether the specific immunogenicity of HSP preparations derives from the peptides chaperoned by the HSPs or by proteins contaminating the HSP preparations. Because absolute purity of a protein preparation is a metaphysical concept, other approaches are necessary to address the question. In this study, we demonstrate that the specific immunogenicity of gp96 preparations isolated from cells expressing β-galactosidase derives from the MHC I epitope precursors associated with the gp96 and not from contaminating β-galactosidase protein nor unassociated fragments derived from it. Although the observations here are limited to a single HSP and antigenic peptides chaperoned by it, they can be extended broadly.
A Novel Approach to Specific Allergy Treatment: The Recombinant Allergen-S-Layer Fusion Protein rSbsC-Bet v 1 Matures Dendritic Cells That Prime Th0/Th1 and IL-10-Producing Regulatory T Cells
Authors: Gerstmayr Marianne , Ilk Nicola , Schabussova Irma , Jahn-Schmid Beatrice , Egelseer Eva M. , Sleytr Uwe B. , Ebner Christof , Bohle Barbara 
Published: April 2014

Abstract
An ideal vaccine for allergen-specific immunotherapy of type I allergies should display reduced mediator-releasing capacity, induce maturation of APC, and modify the disease-eliciting Th2-dominated allergen-specific response to a more physiological response. We have previously shown that rSbsC-Bet v 1, the recombinant fusion protein of a bacterial surface (S-layer) protein of Geobacillus stearothermophilus ATCC 12980 and the major birch pollen allergen Bet v 1, exhibited reduced allergenicity and induced IFN-γ and IL-10 synthesis in Bet v 1-specific Th2 clones. In this study, we characterized the effects of rSbsC-Bet v 1 on immature monocyte-derived dendritic cells (mdDC) and the consequences for the polarization of naive CD4+ T lymphocytes isolated from the blood of birch pollen-allergic patients. mdDC responded to rSbsC-Bet v 1 with a significant up-regulation of costimulatory molecules, functional maturation, and the synthesis of IL-10 and IL-12. mdDC matured with rSbsC-Bet v 1 induced the differentiation of naive T cells into IFN-γ-producing cells. This effect was IL-12 dependent. In parallel, a substantial number of naive T cells developed into IL-10-producing CD25+Foxp3+CLTA-4+ cells capable of active suppression. Thus, rSbsC-Bet v 1 showed immune stimulatory capacity on DC, which then promoted the simultaneous differentiation of Th0/Th1 cells and regulatory T cells. These data further support that the concept of conjugating allergens to bacterial agents is a promising approach to improve vaccines for specific immunotherapy of atopic allergies.
Regulated Expression of BAFF-Binding Receptors during Human B Cell Differentiation
Authors: Darce Jaime R. , Arendt Bonnie K. , Wu Xiaosheng , Jelinek Diane F. 
Published: April 2014

AbstractBAFF plays a central role in B-lineage cell biology; however, the regulation of BAFF-binding receptor (BBR) expression during B cell activation and differentiation is not completely understood. In this study, we provide a comprehensive ex vivo analysis of BBRs in human B-lineage cells at various stages of maturation, as well as describe the events that drive and regulate receptor expression. Our data reveal that B-lineage cells ranging from naive to plasma cells (PCs), excluding bone marrow PCs, express BAFF-R uniformly. In contrast, only tonsillar memory B cells (MB) and PCs, from both tonsil and bone marrow tissues, express BCMA. Furthermore, we show that TACI is expressed by MB cells and PCs, as well as a subpopulation of activated CD27neg B cells. In this regard, we demonstrate that TACI is inducible early upon B cell activation and this is independent of B cell turnover. In addition, we found that TACI expression requires activation of the ERK1/2 pathway, since its expression was blocked by ERK1/2-specific inhibitors. Expression of BAFF-R and B cell maturation Ag (BCMA) is also highly regulated and we demonstrate that BCMA expression is only acquired in MB cells and in a manner accompanied by loss of BAFF-R expression. This inverse expression coincides with MB cell differentiation into Ig-secreting cells (ISC), since blocking differentiation inhibited both induction of BCMA expression and loss of BAFF-R. Collectively, our data suggest that the BBR profile may serve as a footprint of the activation history and stage of differentiation of normal human B cells.
Murine Gammaherpesvirus-68 Infection Alters Self-Antigen Presentation and Type 1 Diabetes Onset in NOD Mice
Authors: Smith Katherine A. , Efstathiou Stacey , Cooke Anne 
Published: April 2014

Abstract
Recent research in line with the “hygiene hypothesis” has implicated virus infection in the delay or prevention of autoimmunity in murine models of type 1 diabetes such as the NOD mouse. We found that intraperitoneal or intranasal infection of NOD mice with the murine gammaherpesvirus-68 (MHV-68) significantly delayed diabetes onset in an age-dependent manner. The acute phase following intraperitoneal infection was associated with significantly reduced trafficking of autoreactive BDC2.5NOD CD4+ T cells to the pancreas but not the pancreatic lymph node (PLN); this was not as a result of MHV-68 M3 pan-chemokine binding protein expression. Autoreactive BDC2.5NOD CD4+ T cells within the PLN of MHV-68 infected mice were significantly more naive and proliferated to a lesser extent than those cells within the PLN of uninfected mice. These changes in autoreactive CD4+ T cell activation were associated with reduced dendritic cell endocytosis and soluble Ag presentation but were not as a result of virally induced IL-10 or changes in Ag-specific regulatory T cell populations.
PECAM-1 Ligation Negatively Regulates TLR4 Signaling in Macrophages
Authors: Rui Yuxiang , Liu Xingguang , Li Nan , Jiang Yingming , Chen Guoyou , Cao Xuetao , Wang Jianli 
Published: April 2014

Abstract
Uncontrolled TLR4 signaling may induce excessive production of proinflammatory cytokines and lead to harmful inflammation; therefore, negative regulation of TLR4 signaling attracts much attention now. PECAM-1, a member of Ig-ITIM family, can mediate inhibitory signals in T cells and B cells. However, the role and the mechanisms of PECAM-1 in the regulation of TLR4-mediated LPS response in macrophages remain unclear. In this study, we demonstrate that PECAM-1 ligation with CD38-Fc fusion protein negatively regulates LPS-induced proinflammatory cytokine TNF-α, IL-6, and IFN-β production by inhibiting JNK, NF-κB, and IFN regulatory factor 3 activation in macrophages. In addition, PECAM-1 ligation-recruited Src homology region 2 domain-containing phosphatase 1 (SHP-1) and Src homology region 2 domain-containing phosphatase 2 (SHP-2) may be involved in the inhibitory effect of PECAM-1 on TLR4 signaling. Consistently, silencing of PECAM-1 enhances the macrophage response to LPS stimulation. Taken together with the data that PECAM-1 is constitutively expressed in macrophages and its expression is up-regulated by LPS stimulation, PECAM-1 might function as a feedback negative regulator of LPS inflammatory response in macrophages. This study may provide a potential target for intervention of inflammatory diseases.
CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells
Authors: Diaz-Guerra Eva , Vernal Rolando , del Prete M. Julieta , Silva Augusto , Garcia-Sanz Jose A. 
Published: April 2014

Abstract
The precise mechanisms involved in the switch between the clonal expansion and contraction phases of a CD8+ T cell response remain to be fully elucidated. One of the mechanisms implicated in the contraction phase is cytokine deprivation, which triggers apoptosis in these cells. CCR2 chemokine receptor is up-regulated following IL-2 deprivation, and its ligand CCL2 plays an essential role preventing apoptosis induced by IL-2 withdrawal not only in CTLL2 cells, but also in mouse Ag-activated primary CD8+ T cells because it rescued functional CD8+ T cells from deprivation induced apoptosis, promoting proliferation in response to subsequent addition of IL-2 or to secondary antigenic challenges. Thus, up-regulation of the CCR2 upon growth factor withdrawal together with the protective effects of CCL2, represent a double-edged survival strategy, protecting cells from apoptosis and enabling them to migrate toward sites where Ag and/or growth factors are available.
Pivotal Roles of CD4+ Effector T cells in Mediating Agonistic Anti-GITR mAb-Induced-Immune Activation and Tumor Immunity in CT26 Tumors
Authors: Zhou Pengfei , L’italien Lawrence , Hodges Douglas , Schebye Xiao Min 
Published: April 2014

Abstract
Glucocorticoid-induced TNF receptor family related protein (GITR) is a member of the TNFR superfamily. Previous studies have shown that in vivo administration of a GITR agonistic Ab (DTA-1) is able to overcome tolerance and induce tumor rejection in several murine syngeneic tumor models. However, little is known about the in vivo targets and the mechanisms of how this tolerance is overcome in a tumor-bearing host, nor is much known about how the immune network is regulated to achieve this antitumor response. In this study, we demonstrate that the in vivo ligation of GITR on CD4+ effector T cells renders them refractory to suppression by regulatory T (Treg) cells in the CT26 tumor-bearing mouse. GITR engagement on Treg cells does not appear to directly abrogate their suppressive function; rather, it increases the expansion of Treg cells and promotes IL-10 production, a cytokine important for their suppressive function. Moreover, CD4+ effector T cells play a crucial role in mediating DTA-1-induced immune activation and expansion of CD8+, NK, and B cells in the tumor-draining lymph nodes. This includes increased CD69 expression on all of these subsets. In addition, NK and tumor-specific CD8+ T cells are generated that are cytolytic, which show increased intracellular IFN-γ production and CD107a mobilization, the latter a hallmark of cytolytic activities that lead to tumor killing.
Activation of Immature Hepatic NK Cells As Immunotherapy for Liver Metastatic Disease
Authors: Bahjat Keith S. , Prell Rodney A. , Allen Heather E. , Liu Weiqun , Lemmens Edward E. , Leong Meredith L. , Portnoy Daniel A. , Dubensky Thomas W. , Brockstedt Dirk G. , Giedlin Martin A. 
Published: April 2014

Abstract
NK cells can identify and eliminate emerging tumors due to altered expression of activating and inhibitory ligands on aberrant cells, a process that is greatly enhanced following NK cell activation. As a principal site of both tumor metastases and immature NK cells, the liver represents a unique anatomic location in which activation of the innate immune system could provide substantial therapeutic benefit. We describe here the NK cell-dependent destruction of a primary hepatic tumor following infection with an attenuated intracellular bacterium derived from Listeria monocytogenes. NK cell-mediated immunity correlated with the ordered migration and maturation of NK cells within the liver. Cytolytic activity was partially dependent on NKG2D-mediated tumor cell recognition, but surprisingly was still effective in the absence of type I IFN. Significantly, NK cell-mediated destruction of a primary hepatic tumor in infected mice led to long-lived CD4- and CD8 T cell-dependent tumor-specific adaptive immunity. These findings establish that activation and differentiation of immature NK cells using complex microbial stimuli can elicit potent anti-tumor activity within the liver, promote cross-presentation of tumor-derived Ags leading to long-lived systemic anti-tumor immunity, and suggests a paradigm for clinical intervention of liver metastatic carcinoma.
Functional Outcome of B Cell Activation by Chromatin Immune Complex Engagement of the B Cell Receptor and TLR9
Authors: Busconi Liliana , Bauer Jason W. , Tumang Joseph R. , Laws Amy , Perkins-Mesires Kristin , Tabor Abigail S. , Lau Christina , Corley Ronald B. , Rothstein Thomas L. , Lund Frances E. , Behrens Timothy W. , Marshak-Rothstein Ann 
Published: April 2014

Abstract
We have previously shown that rheumatoid factors produced by Fas-deficient autoimmune-prone mice typically bind autologous IgG2a with remarkably low affinity. Nevertheless, B cells representative of this rheumatoid factor population proliferate vigorously in response to IgG2a/chromatin immune complexes through a mechanism dependent on the sequential engagement of the BCR and TLR9. To more precisely address the role of both receptors in this response, we analyzed the signaling pathways activated in AM14 B cells stimulated with these complexes. We found that the BCR not only serves to direct the chromatin complex to an internal compartment where it can engage TLR9 but also transmits a suboptimal signal that in combination with the signals emanating from TLR9 leads to NF-κB activation and proliferation. Importantly, engagement of both receptors leads to the up-regulation of a group of gene products, not induced by the BCR or TLR9 alone, that include IL-2. These data indicate that autoreactive B cells, stimulated by a combination of BCR and TLR9 ligands, acquire functional properties that may contribute to the activation of additional cells involved in the autoimmune disease process.
Sensitive Gene Expression Profiling of Human T Cell Subsets Reveals Parallel Post-Thymic Differentiation for CD4+ and CD8+ Lineages
Authors: Appay Victor , Bosio Andreas , Lokan Stefanie , Wiencek Yvonne , Biervert Christian , Küsters Daniel , Devevre Estelle , Speiser Daniel , Romero Pedro , Rufer Nathalie , Leyvraz Serge 
Published: April 2014

Abstract
The differentiation of CD4+ or CD8+ T cells following priming of naive cells is central in the establishment of the immune response against pathogens or tumors. However, our understanding of this complex process and the significance of the multiple subsets of differentiation remains controversial. Gene expression profiling has opened new directions of investigation in immunobiology. Nonetheless, the need for substantial amount of biological material often limits its application range. In this study, we have developed procedures to perform microarray analysis on amplified cDNA from low numbers of cells, including primary T lymphocytes, and applied this technology to the study of CD4 and CD8 lineage differentiation. Gene expression profiling was performed on samples of 1000 cells from 10 different subpopulations, defining the major stages of post-thymic CD4+ or CD8+ T cell differentiation. Surprisingly, our data revealed that while CD4+ and CD8+ T cell gene expression programs diverge at early stages of differentiation, they become increasingly similar as cells reach a late differentiation stage. This suggests that functional heterogeneity between Ag experienced CD4+ and CD8+ T cells is more likely to be located early during post-thymic differentiation, and that late stages of differentiation may represent a common end in the development of T-lymphocytes.
Therapeutic Effect of Anthracene-Based Anticancer Agent Ethonafide in an Animal Model of Multiple Sclerosis
Authors: Piao Wen-Hua , Wong Rudy , Bai Xue-Feng , Huang Jianhua , Campagnolo Denise I. , Dorr Robert T. , Vollmer Timothy L. , Shi Fu-Dong 
Published: April 2014

Abstract
The side effects of cancer chemotherapeutic agents such as mitoxantrone (MIT) in multiple sclerosis (MS) patients justify the search for less toxic drugs. Ethonafide is an anthracene-based antineoplastic drug similar to MIT. With reference to MIT, we examined the effect of ethonafide on experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, an animal model of human MS. We demonstrated that ethonafide is effective in preventing development of EAE as well as in ameliorating the severity of EAE when disease is ongoing. In relatively higher dosages, the effects of ethonafide and MIT on EAE were identical, whereas in lower dosages, MIT seemed more effective. Therapeutic effects of ethonafide were associated with the initial reduction in cellular counts of CD3+, CD4+, CD8+, B220+, CD11b+, NK cells, and NKT cells, followed by recovery of these cells from the bone marrow. Interestingly, the recovered autoreactive T cells in ethonafide-treated animals have reduced capacity to expand and produce cytokines in response to myelin Ag stimulation. Furthermore, CD4+CD25+ regulatory T cells were relatively resistant to depletion and/or recovered faster than T effector cells. The ability of regulatory T cells to resist depletion and replenish quickly during cell ablation therapy may provide an opportunity to reprogram the immune system. Moreover, we provided evidences that ethonafide has less cardiac toxicity compared with MIT. The effectiveness and the low cardiotoxicity of ethonafide might make it a promising immunosuppressive agent for clinical use in treating MS patients.