bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drastic Up-Regulation of FcεRI on Mast Cells Is Induced by IgE Binding Through Stabilization and Accumulation of FcεRI on the Cell Surface
Authors: Kubo Shuichi , Matsuoka Kunie , Taya Choji , Kitamura Fujiko , Takai Toshiyuki , Yonekawa Hiromichi , Karasuyama Hajime 
Published: April 2014

AbstractIt has been shown that IgE binding to FcεRI on mast cells results in increased FcεRI expression, which in turn enhances IgE-dependent chemical mediator release from mast cells. Therefore, prevention of the IgE-mediated FcεRI up-regulation would be a promising strategy for management of allergic disorders. However, the mechanism of IgE-mediated FcεRI up-regulation has not been fully elucidated. In this study, we analyzed kinetics of FcεRI on peritoneal mast cells and bone marrow-derived mast cells. In the presence of brefeldin A, which prevented transport of new FcεRI molecules to the cell surface, levels of IgE-free FcεRI on mast cells decreased drastically during culture, whereas those of IgE-bound FcεRI were stable. In contrast, levels of FcγRIII on the same cells were stable even in the absence of its ligand, indicating that FcεRI α-chain, but not β- and γ-chains, was responsible for the instability of IgE-free FcεRI. As far as we analyzed, there was no evidence to support the idea that IgE binding to FcεRI facilitated synthesis and/or transport of FcεRI to the cell surface. Therefore, the stabilization and accumulation of FcεRI on the cell surface through IgE binding appears to be the major mechanism of IgE-mediated FcεRI up-regulation.
The IL-6-Soluble IL-6Rα Autocrine Loop of Endothelial Activation as an Intermediate Between Acute and Chronic Inflammation: an Experimental Model Involving Thrombin
Authors: Marin Valérie , Montero-Julian Felix A. , Grès Sandra , Boulay Vera , Bongrand Pierre , Farnarier Catherine , Kaplanski Gilles 
Published: April 2014

AbstractThrombin is a procoagulant and proinflammatory molecule in vivo. In vitro, thrombin has been shown to induce endothelial activation, notably IL-8 secretion and adhesion molecule expression. In this study, we showed that thrombin may induce a new cascade leading from acute to chronic inflammation. Thrombin was able to induce the production of both IL-6 and monocyte chemotactic protein-1 (MCP-1) by HUVEC independently of IL-1αβ and TNF-α. Addition of physiological concentrations of exogenous soluble IL-6Rα (sIL-6Rα) to thrombin-activated HUVEC was sufficient to increase the amounts of MCP-1 produced, but not those of IL-8. These effects could be blocked by anti-IL-6 or anti-sIL-6Rα blocking mAb, demonstrating the existence of an autocrine loop of MCP-1 secretion, involving the IL-6/IL-6Rα/gp130 complex on HUVEC. In addition, we identified IL-8-activated neutrophils as a potential source of sIL-6Rα because IL-8 induced IL-6Rα shedding from the neutrophil membranes and increased in parallel sIL-6Rα concentrations in neutrophil supernatants. Furthermore, addition of neutrophils to thrombin-activated HUVEC significantly increased MCP-1 secretion, which could be decreased by blocking IL-6. Thus, thrombin-activated endothelium may induce a cascade of events characterized by IL-8 secretion, neutrophil local infiltration, and the release of IL-6Rα from neutrophil membranes. sIL-6Rα may then complex with IL-6 and increase the amount of MCP-1 produced by thrombin-activated endothelium, favoring monocyte infiltration, and the transformation of acute into chronic inflammation.
IL-3 Induces Down-Regulation of CCR3 Protein and mRNA in Human Eosinophils
Authors: Dulkys Yasmin , Kluthe Christof , Buschermöhle Thomas , Barg Ines , Knöß Sabine , Kapp Alexander , Proudfoot Amanda E. I. , Elsner Jörn 
Published: April 2014

AbstractCytokines and chemokines are responsible for the attraction and activation of eosinophils in allergic and inflammatory diseases. Whereas cytokines such as IL-3, IL-5, and GM-CSF activate eosinophils via heterodimeric receptors containing a distinct α-chain (binding domain) and a common β-chain (signaling domain), chemokines such as eotaxin activate eosinophils via seven-transmembrane Gi protein-coupled CCRs. Recent studies have demonstrated the importance of CCR3 on human eosinophils that undergo receptor recycling after chemokine activation, but the modulation of this receptor by cytokines has not yet been addressed. In this study, we demonstrate that IL-3 induces a dose- and time-dependent down-regulation of CCR3 from the surface of human eosinophils comparable to the CCR3-specific ligand eotaxin, whereas IL-5, GM-CSF, IL-4, IL-10, IL-13, IFN-γ, and TNF-α had no effect. Maximal down-regulation of CCR3 in response to IL-3 was reached at 24 h. Reduction of CCR3 surface protein in response to IL-3 could be prevented by an anti-IL-3 mAb and was neither due to the release of CC chemokines nor to nonspecific binding of IL-3 to CCR3. Moreover, down-regulation was prevented by phenylarsine oxide, a nonspecific inhibitor of receptor internalization. After 24 h, IL-3-induced decrease of CCR3 surface expression correlated with diminished mRNA expression, suggesting a transcriptional regulation mechanism. Since wortmannin partially inhibited IL-3- but not eotaxin-induced CCR3 down-regulation, receptor down-modulation seems to underlie different signaling events. Therefore, these data suggest a novel role for the cytokine IL-3 in the activation process of eosinophils and its predominant chemokine receptor CCR3.
Curcumin Inhibits Activation of Vγ9Vδ2 T Cells by Phosphoantigens and Induces Apoptosis Involving Apoptosis-Inducing Factor and Large Scale DNA Fragmentation
Authors: Cipriani Barbara , Borsellino Giovanna , Knowles Heather , Tramonti Daniela , Cavaliere Fabio , Bernardi Giorgio , Battistini Luca , Brosnan Celia F. 
Published: April 2014

AbstractCurcumin, in addition to its role as a spice, has been used for centuries to treat inflammatory disorders. Although the mechanism of action remains unclear, it has been shown to inhibit the activation of NF-κB and AP-1, transcription factors required for induction of many proinflammatory mediators. Due to its low toxicity it is currently under consideration as a broad anti-inflammatory, anti-tumor cell agent. In this study we investigated whether curcumin inhibited the response of γδ T cells to protease-resistant phosphorylated derivatives found in the cell wall of many pathogens. The results showed that curcumin levels ≥30 μM profoundly inhibited isopentenyl pyrophosphate-induced release of the chemokines macrophage inflammatory protein-1α and -1β and RANTES. Curcumin also blocked isopentenyl pyrophosphate-induced activation of NF-κB and AP-1. Commencing around 16 h, treatment with curcumin lead to the induction of cell death that could not be reversed by APC, IL-15, or IL-2. This cytotoxicity was associated with increased annexin V reactivity, nuclear expression of active caspase-3, cleavage of poly(ADP-ribose) polymerase, translocation of apoptosis-inducing factor to the nucleus, and morphological evidence of nuclear disintegration. However, curcumin led to only large scale DNA chromatolysis, as determined by a combination of TUNEL staining and pulse-field and agarose gel electrophoresis, suggesting a predominantly apoptosis-inducing factor-mediated cell death process. We conclude that γδ T cells activated by these ubiquitous Ags are highly sensitive to curcumin, and that this effect may contribute to the anti-inflammatory properties of this compound.
Midkine Is Involved in Neutrophil Infiltration into the Tubulointerstitium in Ischemic Renal Injury
Authors: Sato Waichi , Kadomatsu Kenji , Yuzawa Yukio , Muramatsu Hisako , Hotta Nigishi , Matsuo Seiichi , Muramatsu Takashi 
Published: April 2014

AbstractMidkine (MK) is a multifunctional heparin-binding protein and promotes migration of neutrophils, macrophages, and neurons. In the normal mouse kidney, MK is expressed in the proximal tubules. After renal ischemic reperfusion injury, its expression in proximal tubules was increased. Immediate increase of MK expression was found when renal proximal tubular epithelial cells in culture were exposed to 5 mM H2O2. Histologically defined tubulointerstitial damage was less severe in MK-deficient (Mdk−/−) than in wild-type (Mdk+/+) mice at 2 and 7 days after ischemic reperfusion injury. Within 2 days after ischemic injury, inflammatory leukocytes, of which neutrophils were the major population, were recruited to the tubulointerstitium. The numbers of infiltrating neutrophils and also macrophages were lower in Mdk−/− than in Mdk+/+ mice. Induction of macrophage inflammatory protein-2 and macrophage chemotactic protein-1, chemokines for neutrophils and macrophages, respectively, were also suppressed in Mdk−/− mice. Furthermore, renal tubular epithelial cells in culture expressed macrophage inflammatory protein-2 in response to exogenous MK administration. These results suggested that MK enhances migration of inflammatory cells upon ischemic injury of the kidney directly and also through induction of chemokines, and contributes to the augmentation of ischemic tissue damage.
The Central Nervous System Inflammatory Response to Neurotropic Virus Infection Is Peroxynitrite Dependent
Authors: Hooper D. Craig , Kean Rhonda B. , Scott Gwen S. , Spitsin Sergei V. , Mikheeva Tatiana , Morimoto Kinjiro , Bette Michael , Röhrenbeck Annette M. , Dietzschold Bernhard , Weihe Eberhard 
Published: April 2014

Abstract
We have recently demonstrated that increased blood-CNS barrier permeability and CNS inflammation in a conventional mouse model of experimental allergic encephalomyelitis are dependent upon the production of peroxynitrite (ONOO−), a product of the free radicals NO· and superoxide (O2·−). To determine whether this is a reflection of the physiological contribution of ONOO− to an immune response against a neurotropic pathogen, we have assessed the effects on adult rats acutely infected with Borna disease virus (BDV) of administration of uric acid (UA), an inhibitor of select chemical reactions associated with ONOO−. The pathogenesis of acute Borna disease in immunocompetent adult rats results from the immune response to the neurotropic BDV, rather than the direct effects of BDV infection of neurons. An important stage in the BDV-specific neuroimmune response is the invasion of inflammatory cells into the CNS. UA treatment inhibited the onset of clinical disease, and prevented the elevated blood-brain barrier permeability as well as CNS inflammation seen in control-treated BDV-infected rats. The replication and spread of BDV in the CNS were unchanged by the administration of UA, and only minimal effects on the immune response to BDV Ags were observed. These results indicate that the CNS inflammatory response to neurotropic virus infection is likely to be dependent upon the activity of ONOO− or its products on the blood-brain barrier.
An Antagonist IL-15/Fc Protein Prevents Costimulation Blockade-Resistant Rejection
Authors: Ferrari-Lacraz Sylvie , Zheng Xin Xiao , Kim Yon Su , Li Yongsheng , Maslinski Wlodzimierz , Li Xian Chang , Strom Terry B. 
Published: April 2014

AbstractIL-15 is a powerful T cell growth factor (TCGF) with particular importance for the maintenance of CD8+ T cells. Because costimulation blockade does not result in universal tolerance, we hypothesized that “escape” from costimulation blockade might represent a CD8+ and IL-15/IL-15R+-dependent process. For this analysis, we have used an IL-15 mutant/Fcγ2a protein, a potentially cytolytic protein that is also a high-affinity receptor site specific antagonist for the IL-15Rα receptor protein, as a therapeutic agent. The IL-15-related fusion protein was used as monotherapy or in combination with CTLA4/Fc in murine islet allograft models. As monotherapies, CTLA4/Fc and an IL-15 mutant/Fcγ2a were comparably effective in a semiallogeneic model system, and combined treatment with IL-15 mutant/Fcγ2a plus CTLA4/Fc produced universal permanent engraftment. In a fully MHC-mismatched strain combination known to be refractory to costimulation blockade treatment, combined treatment with both fusion proteins proved to be highly effective; &gt;70% of recipients were tolerized. The analysis revealed that the IL-15 mutant/Fc treatment confers partial protection from both CD4+ and CD8+ T cell graft infiltration. In rejections occurring despite CTLA4/Fc treatment, concomitant treatment with the IL-15 mutant/Fcγ2a protein blocked a CD8+ T cell-dominated rejection processes. This protection was linked to a blunted proliferative response of alloreactive T cells as well silencing of CTL-related gene expression events. Hence, we have demonstrated that targeting the IL-15/IL-15R pathway represents a new and potent strategy to prevent costimulation blockade-resistant CD8+ T cell-driven rejection.
Terminal Deoxynucleotidyl Transferase Deficiency Decreases Autoimmune Disease in MRL-Fas
lpr Mice
Authors: Feeney Ann J. , Lawson Brian R. , Kono Dwight H. , Theofilopoulos Argyrios N. 
Published: April 2014

Abstract
The neonatal Ab and TCR repertoires are much less diverse, and also very different from, the adult repertoires due to the delayed onset of terminal deoxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontemplated N nucleotides to the junctions of Igs and TCRs, and thus its absence removes one of the major components of junctional diversity in complementarity-determining region 3 (CDR3). We have generated TdT-deficient MRL/lpr, Fas-deficient (MRL-Faslpr) mice, and show that they have an increased lifespan, decreased incidence of skin lesions, and much lower serum levels of anti-dsDNA, anti-chromatin, and IgM rheumatoid factors. The generalized hypergammaglobulinemia characteristic of MRL-Faslpr mice is also greatly reduced, as is the percentage of CD4−CD8−B220+ (double-negative) T cells. IgG deposits in the kidney are significantly reduced, although evidence of renal disease is present in many mice at 6 mo. CDR3 regions of both IgH and TCR from peripheral lymphocytes of MRL-Faslpr mice are shorter in the absence of TdT, and there is a paucity of arginines in the IgH CDR3 regions of the MRL-Faslpr TdT−/− mice. Because the amelioration of symptoms is so widespread, it is likely that the absence of N regions has more of an affect than merely decreasing the precursor frequency of anti-dsDNA B cells. Hence, either the T or B cell repertoires, or more likely both, require N region diversity to produce the full spectrum of autoimmune lupus disease.
Monokine Induced by IFN-γ Is a Dominant Factor Directing T Cells into Murine Cardiac Allografts During Acute Rejection
Authors: Miura Masayoshi , Morita Ken , Kobayashi Hirohito , Hamilton Thomas A. , Burdick Marie D. , Strieter Robert M. , Fairchild Robert L. 
Published: April 2014

AbstractThe use of chemokine antagonism as a strategy to inhibit leukocyte trafficking into inflammatory sites requires identification of the dominant chemokines mediating recruitment. The chemokine(s) directing T cells into cardiac allografts during acute rejection remain(s) unidentified. The role of the CXC chemokines IFN-γ inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig) in acute rejection of A/J (H-2a) cardiac grafts by C57BL/6 (H-2b) recipients was tested. Intra-allograft expression of Mig was observed at day 2 posttransplant and increased to the time of rejection at day 7 posttransplant. IP-10 mRNA and protein production were 2.5- to 8-fold lower than Mig. Whereas allografts were rejected at day 7–9 in control recipients, treatment with rabbit antiserum to Mig, but not to IP-10, prolonged allograft survival up to day 19 posttransplant. At day 7 posttransplant, allografts from Mig antiserum-treated recipients had marked reduction in T cell infiltration. At the time of rejection in Mig antiserum-treated recipients (i.e., days 17–19), intra-allograft expression of macrophage-inflammatory protein-1α, -1β, and their ligand CCR5 was high, whereas expression of CXCR3, the Mig receptor, was virtually absent. Mig was produced by the allograft endothelium as well as by recipient allograft-infiltrating macrophages and neutrophils, indicating the synergistic interactions between innate and adaptive immune compartments during acute rejection. Collectively, these results indicate that Mig is a dominant recruiting factor for alloantigen-primed T cells into cardiac allografts during acute rejection. Although Mig antagonism delays acute heart allograft rejection, the results also suggest that the alloimmune response circumvents Mig antagonism through alternative mechanisms.
IL-10-Deficient B10.Q Mice Develop More Severe Collagen-Induced Arthritis, but Are Protected from Arthritis Induced with Anti-Type II Collagen Antibodies
Authors: Johansson Åsa C. M. , Hansson Ann-Sofie , Nandakumar Kutty S. , Bäcklund Johan , Holmdahl Rikard 
Published: April 2014

AbstractIL-10 is a pleiotropic cytokine with stimulatory and inhibitory properties, and is thought to have a protective role in rheumatoid arthritis and collagen-induced arthritis (CIA). In this study, we investigated how IL-10 deficiency affects CIA and anti-collagen type II (CII) Ab-transferred arthritis in C57BL/10.Q (B10.Q) mice. The B10.Q.IL-10−/− mice had an 8-cM 129/Ola fragment around the IL-10 gene. The mice were treated with antibiotics, appeared healthy, and had no colitis. T cells from IL-10−/− mice expressed similar levels of IFN-γ, IL-2, and IL-4 after mitogen stimulation; however, macrophages showed a reduced TNF-α production compared with IL-10+/− littermates. IL-10−/− mice had an increased incidence, and a more severe CIA disease than the IL-10+/− littermates. To study the role of IL-10 in T cell tolerance, IL-10−/− were crossed into mice carrying the immunodominant epitope, CII(256–270), in cartilage (MMC) or in skin (TSC). Both IL-10−/− and IL-10+/− MMC and TSC mice were completely tolerized against CIA, indicating that lack of IL-10 in this context did not break tolerance. To investigate whether IL-10 was important in the effector phase of CIA, arthritis was induced with anti-CII Abs. Surprisingly, IL-10−/− were less susceptible to Ab-transferred arthritis, as only 30% showed signs of disease compared with 90% of the littermates. Therefore, IL-10 seemed to have a protective role in CIA, but seemed to exacerbate the arthritogenicity of anti-CII Abs. These data emphasize the importance of studying IL-10 in a defined genetic context in vivo, to understand its role in a complex disease like arthritis.
T Cell Activation by Coxsackievirus B4 Antigens in Type 1 Diabetes Mellitus: Evidence for Selective TCR Vβ Usage Without Superantigenic Activity
Authors: Varela-Calvino Ruben , Sgarbi Gianluca , Wedderburn Lucy R. , Dayan Colin M. , Tremble Jenny , Peakman Mark 
Published: April 2014

Abstract
Numerous clinical and epidemiological studies link enteroviruses such as the Coxsackie virus group with the autoimmune disease type 1 diabetes mellitus (DM). In addition, there are reports that patients with type 1 DM are characterized by skewing of TCR Vβ chain selection among peripheral blood and intraislet T lymphocytes. To examine these issues, we analyzed TCR Vβ chain-specific up-regulation of the early T cell activation marker, CD69, on CD4 T cells after incubation with Coxsackievirus B4 (CVB4) Ags. CD4 T cells bearing the Vβ chains 2, 7, and 8 were the most frequently activated by CVB4. Up-regulation of CD69 by different TCR families was significantly more frequent in new onset type 1 DM patients (p = 0.04), 100% of whom (n = 8) showed activation of CD4 T cells bearing Vβ8, compared with 50% of control subjects (n = 8; p = 0.04). T cell proliferation after incubation with CVB4 Ags required live, nonfixed APCs, suggesting that the selective expansion of CD4 T cells with particular Vβ chains resulted from conventional antigen processing and presentation rather than superantigen activity. Heteroduplex analysis of TCR Vβ chain usage after CVB4 stimulation indicated a relatively polyclonal, rather than oligo- or monoclonal response to viral Ags. These results provide evidence that new-onset patients with type 1 DM and healthy controls are primed against CVB4, and that CD4 T cell responses to the virus have a selective TCR Vβ chain usage which is driven by viral Ags rather than a superantigen.
Severe Perturbations of the Blood T Cell Repertoire in Polymyositis, But Not Dermatomyositis Patients
Authors: Benveniste Olivier , Chérin Patrick , Maisonobe Thierry , Merat Rastine , Chosidow Olivier , Mouthon Luc , Guillevin Loïc , Flahault Antoine , Burland Marie-Christine , Klatzmann David , Herson Serge , Boyer Olivier 
Published: April 2014

Abstract
Polymyositis and dermatomyositis are diseases characterized by muscle weakness and muscle inflammatory infiltrates. Their pathogenesis remains unclear. A central role for endomysial autoaggressive CD8+ T cells is suspected in polymyositis and for perivascular B cells in dermatomyositis. We compared the T cell repertoire of 10 polymyositis and 10 dermatomyositis patients by immunoscope, a method providing a global assessment of the T cell repertoire and a sensitive detection of clonal T cell expansions. Samples were analyzed qualitatively and quantitatively in the blood (unsorted cells and CD4+ and CD8+ cells) and in muscle infiltrates. Dramatic perturbations of the T cell repertoire were observed in the blood of polymyositis but not dermatomyositis patients (p &lt; 0.0005), the latter being undistinguishable from controls. These perturbations were due to oligoclonal expansions of CD8+ T cells and most blood clonal expansions were also found in muscle. These results indicate that the pathogenesis of polymyositis and dermatomyositis is different and reinforce the view that polymyositis but not dermatomyositis is an autoimmune CD8+ T cell-mediated disease. Moreover, this method may be helpful for the differential diagnosis of polymyositis and dermatomyositis and for noninvasive follow-up of polymyositis patients.
Redundancy of Direct Priming and Cross-Priming in Tumor-Specific CD8+ T Cell Responses
Authors: Wolkers Monika C. , Stoetter Gerd , Vyth-Dreese Florry A. , Schumacher Ton N. M. 
Published: April 2014

AbstractAgainst a subset of human cancers, vigorous tumor-specific CD8+ T cell responses can develop either spontaneously or upon allogeneic transplantation. However, the parameters that determine the induction of such pronounced anti-tumor immunity remain ill defined. To dissect the conditions required for the induction of high magnitude T cell responses, we have developed a murine model system in which tumor-specific T cell responses can be monitored directly ex vivo by MHC tetramer technology. In this model, tumor challenge of naive mice with Ag-bearing tumor cells results in a massive Ag-specific T cell response, followed by CD8+ T cell-dependent tumor rejection. We have subsequently used this model to assess the contribution of direct priming and cross-priming in the induction of tumor immunity in a well-defined system. Our results indicate that direct priming of T cells and Ag cross-priming are redundant mechanisms for the induction of tumor-specific T cell immunity. Moreover, T cell responses that arise as a consequence of Ag cross-presentation can occur in the absence of CD4+ T cell help and are remarkably robust.