bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Antiproliferative B Cell Translocation Gene-1 as an Apoptotic Sensitizer in Activation-Induced Cell Death of Brain Microglia
Authors: Lee Heasuk , Cha Sanghoon , Lee Myung-Shik , Cho Gyeong Jae , Choi Wan Sung , Suk Kyoungho 
Published: April 2014

Abstract
Mouse brain microglial cells undergo apoptosis on exposure to inflammatory stimuli, which is considered as an autoregulatory mechanism to control their own activation. Here, we present evidence that an antiproliferative B cell translocation gene 1 (BTG1) constitutes a novel apoptotic pathway of LPS/IFN-γ-activated microglia. The expression of BTG1 was synergistically enhanced by LPS and IFN-γ in BV-2 mouse microglial cells as well as in primary microglia cultures. Levels of BTG1 expression inversely correlated with a proliferative capacity of the microglial cells. Tetracycline-based conditional expression of BTG1 not only suppressed microglial proliferation but also increased the sensitivity of microglial cells to NO-induced apoptosis, suggesting a novel mechanism of cooperation between LPS and IFN-γ in the induction of microglial apoptosis. An increase in BTG1 expression, however, did not affect microglial production of NO, TNF-α, or IL-1β, indicating that the antiproliferative BTG1 is important in the activation-induced apoptosis of microglia, but not in the activation itself. The synergistic action of LPS and IFN-γ in the microglial BTG1 induction and apoptosis was dependent on the Janus kinase/STAT1 pathway, but not IFN-regulatory factor-1, as demonstrated by a pharmacological inhibitor of Janus kinase (AG490), STAT1 dominant negative mutant, and IFN-regulatory factor-1-deficient mice. Taken together, antiproliferative BTG1 may participate in the activation-induced cell death of microglia by lowering the threshold for apoptosis; BTG1 increases the sensitivity of microglia to apoptogenic action of autocrine cytotoxic mediator, NO. Our results point out an important link between the proliferative state of microglia and their sensitivity to apoptogenic agents.
Estradiol Treatment Redirects the Isotype of the Autoantibody Response and Prevents the Development of Autoimmune Arthritis
Authors: Latham Kary A. , Zamora Alex , Drought Heather , Subramanian Sandhya , Matejuk Agata , Offner Halina , Rosloniec Edward F. 
Published: April 2014

AbstractA number of clinical and experimental observations have been made relating elevated estrogen levels with the amelioration of autoimmune diseases, yet questions remain about the levels required for efficacy as well as the mechanism of disease inhibition. Using the collagen-induced arthritis (CIA) model, we have studied the effects of physiological, sustained levels of 17β-estradiol in preventing the development of autoimmune arthritis and analyzed the changes in the autoimmune response. Using time-release pellets of 17β-estradiol, arthritis development was significantly inhibited in three different strains of CIA-susceptible mice compared with the effect of placebo treatment, and serum estradiol levels similar to those of mice in estrus were found to be equally effective as higher estradiol concentrations. Analysis of the autoimmune response in the estradiol-treated mice indicated that T cell production of IFN-γ was markedly decreased, and significant decreases were also observed in levels of IL-10 and GM-CSF produced by lymph nodes cells from estradiol-treated mice. Although the total IgG anti-CII response was only minimally affected by estrogen treatment, a significant reduction in the levels of IgG2a anti-CII Abs and an increase in the levels of IgG1 anti-CII Abs were observed in estradiol-treated mice. These data indicate that estradiol treatment altered the Th profile of the autoimmune T cell response, which, in turn, altered the production of IgG Abs to an isotype that is poor at fixing complement, an important component in the immunopathogenesis of CIA.
Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells
Authors: Burchill Matthew A. , Goetz Christine A. , Prlic Martin , O’Neil Jennifer J. , Harmon Ian R. , Bensinger Steven J. , Turka Laurence A. , Brennan Paul , Jameson Stephen C. , Farrar Michael A. 
Published: April 2014

AbstractUsing transgenic mice that express a constitutively active version of STAT5b, we demonstrate that STAT5 plays a key role in governing B cell development and T cell homeostasis. STAT5 activation leads to a 10-fold increase in pro-B, but not pro-T, cells. Conversely, STAT5 signaling promotes the expansion of mature αβ T cells (6-fold increase) and γδ and NK T cells (3- to 4-fold increase), but not of mature B cells. In addition, STAT5 activation has dramatically divergent effects on CD8+ vs CD4+ T cells, leading to the selective expansion of CD8+ memory-like T cells and CD4+CD25+ regulatory T cells. These results establish that activation of STAT5 is the primary mechanism underlying both IL-7/IL-15-dependent homeostatic proliferation of naive and memory CD8+ T cells and IL-2-dependent development of CD4+CD25+ regulatory T cells.
IL-4 and IL-13 InduceSOCS-1Gene Expression in A549 Cells by Three Functional STAT6-Binding Motifs Located Upstream of the Transcription Initiation Site
Authors: Hebenstreit Daniel , Luft Petra , Schmiedlechner Angela , Regl Gerhard , Frischauf Anna-Maria , Aberger Fritz , Duschl Albert , Horejs-Hoeck Jutta 
Published: April 2014

AbstractProteins of the suppressors of cytokine signaling (SOCS) family have important functions as negative regulators of cytokine signaling. We show here that SOCS-1 expression can be induced in the human epithelial lung cell line A549 by IL-4 and IL-13. Analysis of reporter gene constructs under control of the SOCS-1 promoter provides evidence that IL-4- and IL-13-induced up-regulation is dependent on three IFN-γ-activated sequence motifs of the sequence TTC(N)4GAA, which is known for binding STAT6. The three motifs are situated close to each other ∼600 bp upstream of the transcriptional initiation site. When mutations were inserted into all three IFN-γ-activated sequence motifs at the same time, IL-4-IL-13-induced luciferase activity was abrogated. With single and double mutants, promoter activity was diminished in comparison with the wild-type promoter. STAT6 is therefore required for IL-4-IL-13-dependent SOCS-1 expression in A549 cells, and the three identified binding motifs cooperate to induce maximal transcription. EMSAs conducted with nuclear extracts of IL-4- and IL-13-stimulated A549 cells showed that STAT6 was able to bind to each of the three binding motifs. Finally, cotransfection of a SOCS-1 expression vector inhibited activation of SOCS-1 promoter luciferase constructs. Thus, SOCS-1 is able to autoregulate its expression via a negative feedback loop.
CD4+/CD25+ Regulatory Cells Inhibit Activation of Tumor-Primed CD4+ T Cells with IFN-γ-Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination
Authors: Casares Noelia , Arribillaga Laura , Sarobe Pablo , Dotor Javier , Lopez-Diaz de Cerio Ascensión , Melero Ignacio , Prieto Jesús , Borrás-Cuesta Francisco , Lasarte Juan J. 
Published: April 2014

AbstractCD25+ regulatory T (T reg) cells suppress the activation/proliferation of other CD4+ or CD8+ T cells in vitro. Also, down-regulation of CD25+ T reg cells enhance antitumor immune responses. In this study, we show that depletion of CD25+ T reg cells allows the host to induce both CD4+ and CD8+ antitumoral responses following tumor challenge. Simultaneous depletion of CD25+ and CD8+ cells, as well as adoptive transfer experiments, revealed that tumor-specific CD4+ T cells, which emerged in the absence of CD25+ T reg cells, were able to reject CT26 colon cancer cells, a MHC class II-negative tumor. The antitumoral effect mediated by CD4+ T cells was dependent on IFN-γ production, which exerted a potent antiangiogenic activity. The capacity of the host to mount this antitumor response is lost once the number of CD25+ T reg cells is restored over time. However, CD25+ T reg cell depletion before immunization with AH1 (a cytotoxic T cell determinant from CT26 tumor cells) permits the induction of a long-lasting antitumoral immune response, not observed if immunization is conducted in the presence of regulatory cells. A study of the effect of different levels of depletion of CD25+ T reg cells before immunization with the peptide AH1 alone, or in combination with a Th determinant, unraveled that Th cells play an important role in overcoming the suppressive effect of CD25+ T reg on the induction of long-lasting cellular immune responses.
Promiscuity of MHC Class Ib-Restricted T Cell Responses
Authors: Ploss Alexander , Lauvau Gregoire , Contos Brian , Kerksiek Kristen M. , Guirnalda Patrick D. , Leiner Ingrid , Lenz Laurel L. , Bevan Michael J. , Pamer Eric G. 
Published: April 2014

Abstract
Murine infection with the Gram-positive intracellular bacterium Listeria monocytogenes activates CD8+ T cells that recognize bacterially derived N-formyl methionine peptides in the context of H2-M3 MHC class Ib molecules. Three peptides, fMIGWII, fMIVIL, and fMIVTLF, are targets of L. monocytogenes-specific CD8+ T cells. To investigate epitope cross-recognition by H2-M3-restricted CD8+ T cells, we deleted the sequence encoding fMIGWII from a virulent strain of L. monocytogenes. Infection with fMIGWII-deficient L. monocytogenes unexpectedly primed CD8+ T cells that stain with fMIGWII/H2-M3 tetramers and lyse fMIGWII-coated target cells in vivo. Because the fMIGWII sequence is nonredundant, we speculated that other bacterially derived Ags are priming these responses. HPLC peptide fractionation of bacterial culture supernatants revealed several distinct L. monocytogenes-derived peptides that are recognized by fMIGWII-specific T cells. Our results demonstrate that the dominant H2-M3-restricted CD8+ T cell population, although reactive with fMIGWII, is primed by other, non-fMIGWII peptides derived from L. monocytogenes. Although this degree of Ag receptor promiscuity is unusual for the adaptive immune system, it may be a more common feature of T cell responses restricted by nonpolymorphic MHC class Ib molecules.
Allogeneic T Cells Treated with Amotosalen Prevent Lethal Cytomegalovirus Disease without Producing Graft-versus-Host Disease Following Bone Marrow Transplantation
Authors: Roback John D. , Hossain Mohammad S. , Lezhava Levan , Gorechlad John W. , Alexander Sabina A. , Jaye David L. , Mittelstaedt Stephen , Talib Sohel , Hearst John E. , Hillyer Christopher D. , Waller Edmund K. 
Published: April 2014

AbstractInfusion of donor antiviral T cells can provide protective immunity for recipients of hemopoietic progenitor cell transplants, but may cause graft-vs-host disease (GVHD). Current methods of separating antiviral T cells from the alloreactive T cells that produce GVHD are neither routine nor rapid. In a model of lethal murine CMV (MCMV) infection following MHC-mismatched bone marrow transplantation, infusion of MCMV-immune donor lymphocytes pretreated with the DNA cross-linking compound amotosalen prevented MCMV lethality without producing GVHD. Although 95% of mice receiving 30 × 106 pretreated donor lymphocytes survived beyond day +100 without MCMV disease or GVHD, all mice receiving equivalent numbers of untreated lymphocytes rapidly died of GVHD. In vitro, amotosalen blocked T cell proliferation without suppressing MCMV peptide-induced IFN-γ production by MCMV-primed CD8+ T cells. In vivo, pretreated lymphocytes reduced hepatic MCMV load by 4-log10 and promoted full hemopoietic chimerism. Amotosalen-treated, MCMV tetramer-positive memory (CD44high) CD8+ T cells persisted to day +100 following infusion, and expressed IFN-γ when presented with viral peptide. Pretreated T cells were effective at preventing MCMV lethality over a wide range of concentrations. Thus, amotosalen treatment rapidly eliminates the GVHD activity of polyclonal T cells, while preserving long-term antiviral and graft facilitation effects, and may be clinically useful for routine adoptive immunotherapy.
Cross-Talk in the Innate Immune System: Neutrophils Instruct Recruitment and Activation of Dendritic Cells during Microbial Infection
Authors: Bennouna Soumaya , Bliss Susan K. , Curiel Tyler J. , Denkers Eric Y. 
Published: April 2014

AbstractType I inflammatory cytokines are essential for immunity to many microbial pathogens, including Toxoplasma gondii. Dendritic cells (DC) are key to initiating type 1 immunity, but neutrophils are also a source of chemokines and cytokines involved in Th1 response ignition. We found that T. gondii triggered neutrophil synthesis of CC chemokine ligand (CCL)3, CCL4, CCL5, and CCL20, chemokines that were strongly chemotactic for immature DC. Moreover, supernatants obtained from parasite-stimulated polymorphonuclear leukocytes induced DC IL-12(p40) and TNF-α production. Parasite-triggered neutrophils also released factors that induced DC CD40 and CD86 up-regulation, and this response was dependent upon parasite-triggered neutrophil TNF-α production. In vivo evidence that polymorphonuclear leukocytes exert an important influence on DC activation was obtained by examining splenic DC cytokine production following infection of neutrophil-depleted mice. These animals displayed severely curtailed splenic DC IL-12 and TNF-α production, as revealed by ex vivo flow cytometric analysis and in vitro culture assay. Our results reveal a previously unrecognized regulatory role for neutrophils in DC function during microbial infection, and suggest that cross-talk between these cell populations is an important component of the innate immune response to infection.
Sustained Nitric Oxide Delivery Delays Nitric Oxide-Dependent Apoptosis in Macrophages: Contribution to the Physiological Function of Activated Macrophages
Authors: Hortelano Sonsoles , Través Paqui G. , Zeini Miriam , Alvarez Alberto M. , Boscá Lisardo 
Published: April 2014

Abstract
Treatment of the macrophage cell line RAW 264.7 with the short-lived NO donor S-nitrosoglutathione triggers apoptosis through the release of mitochondrial mediators. However, continuous supply of NO by long-lived NO donors protected cells from apoptosis through mechanisms that involved the maintenance or an increase in the levels of the inhibitor of apoptosis proteins (IAPs) cIAP-1, cIAP-2, and xIAP and decreases in the accumulation of p53 and in the levels and targeting of Bax to the mitochondria. As a result of these changes, the activation of caspases 9 and 3 was notably delayed, expanding the time of viability of the macrophages. Moreover, inhibition of NO synthase 2 activity after 8 h of stimulation of RAW 264.7 cells with LPS and IFN-γ accelerated apoptosis via an increase in the processing and activation of caspases. These data suggest that NO exerts an important role in the autoregulation of apoptosis in macrophages.
Curcumin Suppresses Janus Kinase-STAT Inflammatory Signaling through Activation of Src Homology 2 Domain-Containing Tyrosine Phosphatase 2 in Brain Microglia
Authors: Kim Hee Young , Park Eun Jung , Joe Eun-hye , Jou Ilo 
Published: April 2014

AbstractCurcumin has been strongly implicated as an anti-inflammatory agent, but the precise mechanisms of its action are largely unknown. In this study, we show that the inhibitory action of curcumin on Janus kinase (JAK)-STAT signaling can contribute to its anti-inflammatory activity in the brain. In both rat primary microglia and murine BV2 microglial cells, curcumin effectively suppressed the ganglioside-, LPS-, or IFN-γ-stimulated induction of cyclooxygenase-2 and inducible NO synthase, important enzymes that mediate inflammatory processes. These anti-inflammatory effects appear to be due, at least in part, to the suppression of the JAK-STAT inflammatory signaling cascade. Curcumin markedly inhibited the phosphorylation of STAT1 and 3 as well as JAK1 and 2 in microglia activated with gangliosides, LPS, or IFN-γ. Curcumin consistently suppressed not only NF binding to IFN-γ-activated sequence/IFN-stimulated regulatory element, but also the expression of inflammation-associated genes, including ICAM-1 and monocyte chemoattractant protein 1, whose promoters contain STAT-binding elements. We further show that activation of Src homology 2 domain-containing protein tyrosine phosphatases (SHP)-2, a negative regulator of JAK activity, is likely to be one of the mechanisms underlying the curcumin-mediated inhibition of JAK-STAT signaling. Treatment of microglial cells with curcumin led to an increase in phosphorylation and association with JAK1/2 of SHP-2, which inhibit the initiation of JAK-STAT inflammatory signaling in activated microglia. Taken together, these data suggest curcumin suppresses JAK-STAT signaling via activation of SHP-2, thus attenuating inflammatory response of brain microglial cells.
Cyclooxygenase-2-Derived E Prostaglandins Down-Regulate Matrix Metalloproteinase-1 Expression in Fibroblast-Like Synoviocytes via Inhibition of Extracellular Signal-Regulated Kinase Activation
Authors: Pillinger Michael H. , Rosenthal Pamela B. , Tolani Sonia N. , Apsel Beth , Dinsell Victoria , Greenberg Jeffrey , Chan Edwin S. L. , Gomez Paul F. , Abramson Steven B. 
Published: April 2014

Abstract
We examined the regulation of matrix metalloproteinase (MMP) production by mitogen-activated protein kinases and cyclooxygenases (COXs) in fibroblast-like synoviocytes (FLSCs). IL-1β and TNF-α stimulated FLSC extracellular signal-regulated kinase (ERK) activation as well as MMP-1 and -13 release. Pharmacologic inhibitors of ERK inhibited MMP-1, but not MMP-13 expression. Whereas millimolar salicylates inhibited both ERK and MMP-1, nonsalicylate COX and selective COX-2 inhibitors enhanced stimulated MMP-1 release. Addition of exogenous PGE1 or PGE2 inhibited MMP-1, reversed the effects of COX inhibitors, and inhibited ERK activation, suggesting that COX-2 activity tonically inhibits MMP-1 production via ERK inhibition by E PGs. Exposure of FLSCs to nonselective COX and selective COX-2 inhibitors in the absence of stimulation resulted in up-regulation of MMP-1 expression in an ERK-dependent manner. Moreover, COX inhibition sufficient to reduce PGE levels increased ERK activity. Our data indicate that: 1) ERK activation mediates MMP-1 but not MMP-13 release from FLSCs, 2) COX-2-derived E PGs inhibit MMP-1 release from FLSCs via inhibition of ERK, and 3) COX inhibitors, by attenuating PGE inhibition of ERK, enhance the release of MMP-1 by FLSC.
Mac-1, but Not LFA-1, Uses Intercellular Adhesion Molecule-1 to Mediate Slow Leukocyte Rolling in TNF-α-Induced Inflammation
Authors: Dunne Jessica L. , Collins Robert G. , Beaudet Arthur L. , Ballantyne Christie M. , Ley Klaus 
Published: April 2014

AbstractWe have previously shown that Mac-1 and LFA-1 play a cooperative role in slow leukocyte rolling in inflamed vessels, and that, although both have a role in leukocyte adhesion, the contribution from LFA-1 exceeds that of Mac-1. In this study, we used mice deficient in ICAM-1 (ICAM-1null) to study the function of ICAM-1 as an endothelial ligand for Mac-1 and LFA-1. The cremaster muscles of these mice were treated with TNF-α and prepared for intravital microscopy. We found that the average rolling velocity in venules was not different in ICAM-1null mice (4.7 μm/s) compared with wild-type mice (5.1 μm/s). Similarly, leukocyte adhesion efficiency in ICAM-1null mice (0.11 ± 0.01 mm) was similar to that in Mac-1−/− (0.12 ± 0.03 mm) mice but significantly increased compared with that in LFA-1−/− (0.08 ± 0.01 mm) mice and significantly reduced from that in wild type (0.26 ± 0.04 mm). When both LFA-1 and ICAM-1 were blocked, rolling velocity increased, and adhesion efficiency and arrest decreased. However, blocking both Mac-1 and ICAM-1 had no greater effect than either blockade alone. We conclude that endothelial ICAM-1 is the main ligand responsible for slow leukocyte rolling mediated by Mac-1, but not LFA-1.
Regulation and Phenotype of an Innate Th1 Cell: Role of Cytokines and the p38 Kinase Pathway
Authors: Yu Jeffrey J. , Tripp Catherine S. , Russell John H. 
Published: April 2014

Abstract
We have explored the phenotype and regulation of Th1 cell activation by the cytokines IL-12 and IL-18. We demonstrate that these two cytokines selectively induce IFN-γ in a differentiated Th1 cell population through the previously described p38 mitogen-activated protein (MAP) kinase pathway. Using a highly selective p38 MAP kinase inhibitor, we demonstrate that it is possible to block IFN-γ induction from activated, differentiated Th1 cells via p38 MAP kinase without disrupting the activation and differentiation of naive T cells or the proliferation of naive or differentiated T cells. In addition, IL-12 and IL-18 provide an Ag and IL-2-independent survival signal to this uniquely differentiated Th1 cell population. We hypothesize that this Ag-independent survival of Th1 cells may participate in an innate inflammatory loop with monocytes at the sites of chronic inflammation. In addition, p38 MAP kinase inhibition of this cytokine-regulated pathway may be a unique mechanism to inhibit chronic inflammation without disruption of Ag-driven activation and function of naive T cells.
FcεRI Signaling of Mast Cells Activates Intracellular Production of Hydrogen Peroxide: Role in the Regulation of Calcium Signals
Authors: Suzuki Yoshihiro , Yoshimaru Tetsuro , Matsui Takashi , Inoue Toshio , Niide Osamu , Nunomura Satoshi , Ra Chisei 
Published: April 2014

AbstractEarlier studies, including our own, revealed that activation of mast cells is accompanied by production of reactive oxygen species (ROS) that help to mediate the release of the inflammatory mediators, including histamine and eicosanoids. However, little is known about the mechanisms of ROS production, including the species of oxidants produced. In this study we show that in both the RBL-2H3 mast cell line and bone marrow-derived mast cells, FcεRI cross-linking stimulates intracellular oxidative burst, including hydrogen peroxide (H2O2) production, as defined with the oxidant-sensitive dyes dichlorofluorescein and scopoletin and the selective scavenger ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one). The oxidative burst was observed immediately after stimulation and was most likely due to an NAD(P)H oxidase. Experiments using selective pharmacological inhibitors demonstrated that activation of tyrosine kinases and phosphatidylinositol-3-kinase is required for induction of the oxidative burst. Blockade of the oxidative burst by diphenyleneiodonium impaired the release of preformed granular mediators, such as histamine and β-hexosaminidase, and the secretion of newly synthesized leukotriene C4, whereas selective scavenging H2O2 by ebselen impaired leukotriene C4 secretion, but not degranulation. Sustained elevation of cytosolic calcium through store-operated calcium entry was totally abolished when ROS production was blocked. In contrast, selective depletion of H2O2 caused a considerable decrease and delay of the calcium response. Finally, tyrosine phosphorylation of phospholipase Cγ and the linker for activation of T cells, an event required for calcium influx, was suppressed by diphenyleneiodonium and ebselen. These studies demonstrate that activation of the intracellular oxidative burst is an important regulatory mechanism of mast cell responses.