bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGF-β and Smad3 Signaling Link Inflammation to Chronic Fibrogenesis
Authors: Bonniaud Philippe , Margetts Peter J. , Ask Kjetil , Flanders Kathy , Gauldie Jack , Kolb Martin 
Published: April 2014

Abstract
Transient adenovirus-mediated gene transfer of IL-1β (AdIL-1β), a proinflammatory cytokine, induces marked inflammation and severe and progressive fibrosis in rat lungs. This is associated with an increase in TGF-β1 concentration in bronchoalveolar lavage (BAL) fluid. TGF-β1 is a key cytokine in the process of fibrogenesis, using intracellular signaling pathways involving Smad2 and Smad3. In this study we investigate whether inflammation induced by IL-1β is able to independently induce lung fibrosis in mice deficient in the Smad3 gene. Seven days after AdIL-1β administration, similar levels of IL-1β transgene are seen in BAL in both wild-type (WT) and knockout (KO) mice, and BAL cell profiles demonstrated a similar marked neutrophilic inflammation. Phospho-Smad2 staining was positive in areas of inflammation in both WT and KO mice at day 7. By day 35 after transient IL-1β expression, WT mice showed marked fibrosis in peribronchial areas, quantified by picrosirius red staining and morphometry. However, there was no evidence of fibrosis or collagen accumulation in IL-1β-treated KO mice, and peribronchial areas were not different from KO mice treated with the control adenovector. TGF-β1 and phospho-Smad2 were strongly positive at day 35 in fibrotic areas observed in WT mice, but no such staining was detectable in KO mice. The IL-1β-induced chronic fibrotic response in mouse lungs is dependent on Smad3. KO and WT animals demonstrated a similar inflammatory response to overexpression of IL-1β indicating that inflammation must link to the Smad3 pathway, likely through TGF-β, to induce progressive fibrosis.
Altered CXCR2 Signaling in β-Arrestin-2-Deficient Mouse Models
Authors: Su Yingjun , Raghuwanshi Sandeep K. , Yu Yingchun , Nanney Lillian B. , Richardson Ricardo M. , Richmond Ann 
Published: April 2014

Abstract
CXCR2 is a G-protein-coupled receptor (GPCR) that binds the CXC chemokines, CXCL1–3 and CXCL5–8, and induces intracellular signals associated with chemotaxis. Many adaptor proteins are actively involved in the sequestration, internalization, and trafficking of CXCR2 and transduction of agonist-induced intracellular signaling. We have previously shown that adaptor protein β-arrestin-2 (βarr2) plays a crucial role in transducing signals mediated through CXCR2. To further investigate the role of βarr2 on CXCR2-mediated signaling during acute inflammation, zymosan-induced neutrophils were isolated from peritoneal cavities of βarr2-deficient (βarr2−/−) and their wild-type (βarr2+/+) littermate mice, and neutrophil CXCR2 signaling activities were determined by measurement of Ca2+ mobilization, receptor internalization, GTPase activity, and superoxide anion production. The results showed that the deletion of βarr2 resulted in increased Ca2+ mobilization, superoxide anion production, and GTPase activity in neutrophils, but decreased receptor internalization relative to wild-type mice. Two animal models, the dorsal air pouch model and the excisional wound healing model, were used to further study the in vivo effects of βarr2 on CXCR2-mediated neutrophil chemotaxis and on cutaneous wound healing. Surprisingly, the recruitment of neutrophils was increased in response to CXCL1 in the air pouch model and in the excisional wound beds of βarr2−/− mice. Wound re-epithelialization was also significantly faster in βarr2−/− mice than in βarr2+/+ mice. Taken together, the data indicate that βarr2 is a negative regulator for CXCR2 in vivo signaling.
The Chemokines CXCL9, CXCL10, and CXCL11 Differentially Stimulate Gαi-Independent Signaling and Actin Responses in Human Intestinal Myofibroblasts
Authors: Kouroumalis Andreas , Nibbs Robert J. , Aptel Herve , Wright Karen L. , Kolios George , Ward Stephen G. 
Published: April 2014

Abstract
Intestinal myofibroblasts have been implicated in the pathogenesis of chronic inflammatory conditions such as Crohn’s disease via interactions with an elaborate network of cytokines, growth factors, and other inflammatory mediators. CXCR3 is a Gαi protein-coupled receptor that binds the proinflammatory chemokines CXCL9, CXCL10, and CXCL11, which are released from the intestinal epithelium. The three CXCR3 ligands shared the ability to activate biochemical (e.g., PI3K and MAPK activation) and functional events (actin reorganization) in intestinal myofibroblasts. However, CXCL11 is unique in its ability to elevate intracellular calcium. Surprisingly, although CXCR3 mRNA is detectable in these myofibroblasts, there is no detectable surface expression of CXCR3. Furthermore, the biochemical responses and actin reorganization stimulated by the CXCR3 ligands in intestinal myofibroblasts are insensitive to the Gαi inhibitor, pertussis toxin. This suggests either the existence of differential receptor coupling mechanisms in myofibroblasts for CXCR3 that are distinct from those observed in PBLs and/or that these cells express a modified or variant CXCR3 compared with the CXCR3 expressed on PBLs.
Carboxylated Glycans Mediate Colitis through Activation of NF-κB
Authors: Srikrishna Geetha , Turovskaya Olga , Shaikh Raziya , Newlin Robbin , Foell Dirk , Murch Simon , Kronenberg Mitchell , Freeze Hudson H. 
Published: April 2014

Abstract
The role of carbohydrate modifications of glycoproteins in leukocyte trafficking is well established, but less is known concerning how glycans influence pathogenesis of inflammation. We previously identified a carboxylate modification of N-linked glycans that is recognized by S100A8, S100A9, and S100A12. The glycans are expressed on macrophages and dendritic cells of normal colonic lamina propria, and in inflammatory infiltrates in colon tissues from Crohn’s disease patients. We assessed the contribution of these glycans to the development of colitis induced by CD4+CD45RBhigh T cell transfer to Rag1−/− mice. Administration of an anti-carboxylate glycan Ab markedly reduced clinical and histological disease in preventive and early therapeutic protocols. Ab treatment reduced accumulation of CD4+ T cells in colon. This was accompanied by reduction in inflammatory cells, reduced expression of proinflammatory cytokines and of S100A8, S100A9, and receptor for advanced glycation end products. In vitro, the Ab inhibited expression of LPS-elicited cytokines and induced apoptosis of activated macrophages. It specifically blocked activation of NF-κB p65 in lamina propria cells of colitic mice and in activated macrophages. These results indicate that carboxylate-glycan-dependent pathways contribute to the early onset of colitis.
Oxidative Stress Augments the Production of Matrix Metalloproteinase-1, Cyclooxygenase-2, and Prostaglandin E2 through Enhancement of NF-κB Activity in Lipopolysaccharide-Activated Human Primary Monocytes
Authors: Lu Yunbiao , Wahl Larry M. 
Published: April 2014

Abstract
The excessive production of reactive oxidative species (ROS) associated with inflammation leads to a condition of oxidative stress. Cyclooxygenase-2 (COX-2), PGE2, and matrix metalloproteinases (MMPs) are important mediators during the process of inflammation. In this paper we report on studies examining how the ROS hydrogen peroxide (H2O2) affects the production of MMP-1, COX-2, and PGE2. Addition of H2O2 to LPS-activated monocytes, but not naive monocytes, caused a significant enhancement of the LPS-induced production of MMP-1, COX-2, and PGE2. The mechanism by which H2O2 increased these mediators was through enhancement of IκBα degradation, with subsequent increases in NF-κB activation and NF-κB p50 translocation to the nucleus. The effects of H2O2 on IκBα degradation, NF-κB activation, and NF-κB p50 localization to the nucleus were demonstrated through studies of coimmunoprecipitation of IκBα with p50, ELISA of NF-κB p65 activity, and Western blot analysis of the nuclear fraction extract for p50. The key role for NF-κB in this process was demonstrated by the ability of MG-132 or lactacystin (proteasome inhibitors) to block the enhanced production of MMP-1, COX-2, and PGE2. In contrast, indomethacin, which inhibited PGE2 production, partially blocked the enhanced MMP-1 production. Moreover, although PGE2 restored MMP-1 production in indomethacin-treated monocyte cultures; it failed to significantly restore MMP-1 production in proteasome inhibitor-treated cultures. Thus, in the presence of LPS and H2O2, NF-κB plays a dominate role in the regulation of MMP-1, COX-2, and PGE2 expression.
Nonpathogenic, Environmental Fungi Induce Activation and Degranulation of Human Eosinophils
Authors: Inoue Yoshinari , Matsuwaki Yoshinori , Shin Seung-Heon , Ponikau Jens U. , Kita Hirohito 
Published: April 2014

Abstract
Eosinophils and their products are probably important in the pathophysiology of allergic diseases, such as bronchial asthma, and in host immunity to certain organisms. An association between environmental fungal exposure and asthma has been long recognized clinically. Although products of microorganisms (e.g., lipopolysaccharides) directly activate certain inflammatory cells (e.g., macrophages), the mechanism(s) that triggers eosinophil degranulation is unknown. In this study we investigated whether human eosinophils have an innate immune response to certain fungal organisms. We incubated human eosinophils with extracts from seven environmental airborne fungi (Alternaria alternata, Aspergillus versicolor, Bipolaris sorokiniana, Candida albicans, Cladosporium herbarum, Curvularia spicifera, and Penicillium notatum). Alternaria and Penicillium induced calcium-dependent exocytosis (e.g., eosinophil-derived neurotoxin release) in eosinophils from normal individuals. Alternaria also strongly induced other activation events in eosinophils, including increases in intracellular calcium concentration, cell surface expression of CD63 and CD11b, and production of IL-8. Other fungi did not induce eosinophil degranulation, and Alternaria did not induce neutrophil activation, suggesting specificity for fungal species and cell type. The Alternaria-induced eosinophil degranulation was pertussis toxin sensitive and desensitized by preincubating cells with G protein-coupled receptor agonists, platelet-activating factor, or FMLP. The eosinophil-stimulating activity in Alternaria extract was highly heat labile and had an Mr of ∼60 kDa. Thus, eosinophils, but not neutrophils, possess G protein-dependent cellular activation machinery that directly responds to an Alternaria protein product(s). This innate response by eosinophils to certain environmental fungi may be important in host defense and in the exacerbation of inflammation in asthma and allergic diseases.
Vγ9Vδ2 T Cell Response to Colon Carcinoma Cells
Authors: Corvaisier Murielle , Moreau-Aubry Agnès , Diez Elisabeth , Bennouna Jaafar , Mosnier Jean-Francois , Scotet Emmanuel , Bonneville Marc , Jotereau Francine 
Published: April 2014

Abstract
During analysis of CD8 T cells derived from ascites of a colon cancer patient, we isolated a Vγ9Vδ2 T cell clone showing strong reactivity against autologous tumor cell lines. This clone killed a large fraction of allogeneic colon carcinoma and melanoma cell lines, but did not affect a normal colon cell line, colon fibroblasts, or melanocytes. Tumor cell recognition was TCR and NKG2D dependent and induced TNF-α and IFN-γ secretion by the clone; accordingly, tumor targets expressed several NKG2D ligands, such as MHC class I chain-related gene A and UL16-binding protein molecules. Colon tumor recognition by Vγ9Vδ2 T cells was highly dependent on isopentenyl pyrophosphate production and ICAM-1 expression by target cells. Finally, similar reactivity patterns against colon carcinoma cell lines were observed using polyclonal Vγ9Vδ2 T cells of various origins, and Vγ9Vδ2 lymphocytes were present in the majority of colon tumor samples studied. Together, these results suggest that Vγ9Vδ2 T cells contribute to the natural immune surveillance against colon cancers. Therefore, this study provides a strong rationale for the use of Vγ9Vδ2 T cell agonists in immunotherapies targeting colon tumors.
Defined Blocks in Terminal Plasma Cell Differentiation of Common Variable Immunodeficiency Patients
Authors: Taubenheim Nadine , von Hornung Marcus , Durandy Anne , Warnatz Klaus , Corcoran Lynn , Peter Hans-Hartmut , Eibel Hermann 
Published: April 2014

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective Ab production and recurrent bacterial infections. The largely unknown causes are likely to comprise a diverse set of genetic or acquired defects. In this study, we investigated terminal B cell differentiation in lymph nodes from CVID patients. Up to the germinal center B cell stage, B cell differentiation was normal but terminal plasma cell development was found to be impaired. Using differential Blimp-1 and Syndecan-1 expression in controls, we defined three different plasma cell subsets that correspond to progressive developmental stages locating to different sites in the lymph node. In the CVID patients, we could only detect one or two of these subsets indicating a defective differentiation. Thus, terminal plasma cell differentiation was found to be impaired despite normal expression of Blimp-1. B cells reaching only the first stage of plasma cell differentiation were further unable to undergo isotype switching and to up-regulate activation markers on B cells stimulated in vitro.
Requirement for Neutralizing Antibodies to Control Bone Marrow Transplantation-Associated Persistent Viral Infection and to Reduce Immunopathology
Authors: Lang Karl S. , Recher Mike , Navarini Alexander A. , Freigang Stefan , Harris Nicola L. , van den Broek Maries , Odermatt Bernhard , Hengartner Hans , Zinkernagel Rolf M. 
Published: April 2014

Abstract
Bone marrow transplantation (BMT) is commonly used in the treatment of leukemia, however its therapeutic application is partly limited by the high incidence of associated opportunistic infections. We modeled this clinical situation by infecting mice that underwent BMT with lymphocytic choriomeningitis virus (LCMV) and investigated the potential of immunotherapeutic strategies to counter such infections. All mice that received BMT survived LCMV infection and developed a virus carrier status. Immunotherapy by adoptive transfer of naive splenocytes protected against low (200 PFU), but not high (2 × 106 PFU), doses of LCMV. Attempts to control infection of high viral titers using strongly elevated frequencies of activated LCMV-specific T cells failed to control virus and resulted in immunopathology and death. In contrast, virus neutralizing Abs combined with naive splenocytes were able to efficiently control high-dose LCMV infection without associated side effects. Thus, cell transfer combined with neutralizing Abs represented the most effective means of controlling BMT-associated opportunistic viral infection in our in vivo model. These data underscore the in vivo efficacy and immunopathological “safety” of neutralizing antibodies.
Cutting Edge: TRAIL Deficiency Accelerates Hematological Malignancies
Authors: Zerafa Nadeen , Westwood Jennifer A. , Cretney Erika , Mitchell Sally , Waring Paul , Iezzi Manuela , Smyth Mark J. 
Published: April 2014

Abstract
TNF apoptosis-inducing ligand is attracting considerable interest as a potential extrinsic tumor suppressor mechanism, although previous reports have conveyed somewhat contrasting views regarding the likely importance of this pathway. In this study, we provide the first evaluation of spontaneous tumor formation over the life span of TRAIL-deficient mice. Interestingly, &gt;25% of these mice do develop lymphoid malignancies after 500 days of life. TRAIL suppressed the initiation and development of both tumors of lymphoid and stromal origin in the context of the loss of at least one p53 allele. Specific examination of the role of TRAIL in Her2/neu oncogene-driven mammary epithelial cancer revealed no critical role for TRAIL despite the inherent TRAIL sensitivity of such mammary carcinomas. Overall, the data indicate an important function of TRAIL in controlling carcinogenesis, but suggest that further examination of this pathway in epithelial malignancies is warranted.
Cutting Edge: CD4+CD25+ Regulatory T Cells Contribute to Gender Differences in Susceptibility to Experimental Autoimmune Encephalomyelitis
Authors: Reddy Jay , Waldner Hanspeter , Zhang Xingmin , Illes Zsolt , Wucherpfennig Kai W. , Sobel Raymond A. , Kuchroo Vijay K. 
Published: April 2014

Abstract
Female B10.S mice are highly resistant to proteolipid protein (PLP) 139–151-induced experimental autoimmune encephalomyelitis (EAE) and depletion of PLP 139–151-reactive CD4+CD25+ regulatory T (Treg) cells can slightly increase their EAE susceptibility. Although male B10.S mice are moderately susceptible to EAE, we report that depletion of Treg cells in male B10.S mice before immunization with PLP 139–151 renders them highly susceptible to severe EAE with more CNS neutrophil infiltrates than nondepleted controls. Increased susceptibility is associated with an enhanced PLP 139–151-specific T cell response and greater production of IFN-γ, IL-6, and IL-17. Male CD4+CD25− effector cells depleted of Treg cells proliferate to a greater degree than those from females in response to either anti-CD3 or PLP 139–151. These data suggest that because of their capacity to regulate potent autoaggressive effector cells, Treg cells partly contribute to the resistance to autoimmunity in the male mice.
Cutting Edge: A Critical Role for Gene Silencing in Preventing Excessive Type 1 Immunity
Authors: Hutchins Anne S. , Artis David , Hendrich Brian D. , Bird Adrian P. , Scott Phillip , Reiner Steven L. 
Published: April 2014

Abstract
Immunity often depends on proper cell fate choice by helper T lymphocytes. A naive cell, with minimal expression of IFN-γ and IL-4, must give rise to progeny expressing high levels of either one, but not both, of those cytokines to defend against protozoan and helminthic pathogens, respectively. In the present study, we show that inactivation of the Mbd2 gene, which links DNA methylation and repressed chromatin, results in enhanced resistance to the protozoan parasite Leishmania major but impaired immunity to the intestinal helminth Trichuris muris. Helper T cells from methyl CpG-binding domain protein-2-deficient mice exhibit exuberant patterns of cytokine expression despite appropriate silencing of genes encoding the lineage-specifying factors T-bet and GATA-3. These results suggest that gene silencing can facilitate the ability of a progenitor cell to give rise to appropriately differentiated daughter cells in vivo. These findings also point to novel pathways that could participate in genetic control of resistance to infection and autoimmunity.
Cutting Edge: Macrophage Migration Inhibitory Factor Is Necessary for Progression of Experimental Autoimmune Encephalomyelitis
Authors: Powell Nicole D. , Papenfuss Tracey L. , McClain Melanie A. , Gienapp Ingrid E. , Shawler Todd M. , Satoskar Abhay R. , Whitacre Caroline C. 
Published: April 2014

AbstractMacrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of inflammatory and autoimmune diseases. The role of MIF in the progression of experimental autoimmune encephalomyelitis (EAE) was explored using MIF−/− mice. Wild-type mice showed a progressive disease course, whereas MIF−/− mice exhibited acute signs but no further progression of clinical disease. MIF−/− mice displayed markedly elevated corticosterone levels and significant decreases in the inflammatory cytokines TNF-α, IFN-γ, IL-2, and IL-6 before, during, and after EAE onset. Taken together, these findings support that MIF is an important mediator of EAE progression through glucocorticoid antagonism and up-regulation of the inflammatory response.
Cutting Edge: Double-Stranded DNA Breaks in the IgV Region Gene Were Detected at Lower Frequency in Affinity-Maturation Impeded GANP−/− Mice
Authors: Kawatani Yousuke , Igarashi Hideya , Matsui Takeshi , Kuwahara Kazuhiko , Fujimura Satoru , Okamoto Nobukazu , Takagi Katsumasa , Sakaguchi Nobuo 
Published: April 2014

Abstract
Double-stranded DNA breaks (DSBs) at the IgV region (IgV) genes might be involved in somatic hypermutation and affinity-maturation of the B cell receptor in response to T cell-dependent Ag. By ligation-mediated PCR, we studied IgV DSBs that occurred in mature germinal center B cells in response to nitrophenyl-chicken γ-globulin in a RAG1-independent, Ag-dependent, and IgV-selective manner. We quantified their levels in GANP-deficient B cells that have impaired generation of high-affinity Ab. GANP−/− B cells showed a decreased level of DSBs with blunt ends than control B cells and, on the contrary, the ganp gene transgenic (GANPTg) B cells showed an increased level. These results suggested that the level of IgV DSBs in germinal center B cells is associated with GANP expression, which is presumably required for B cell receptor affinity maturation.
Cutting Edge: Memory CD8 T Cell Maturation Occurs Independently of CD8αα
Authors: Chandele Anmol , Kaech Susan M. 
Published: April 2014

Abstract
As memory CD8 T cells form during acute viral infection, several changes in gene expression and function occur, but little is known about the control of this process. It was reported previously that the homodimer CD8αα was involved in generating IL-7Rαhigh memory CD8 T cell precursors, and consequently, protective memory CD8 T cells did not form in animals significantly impaired in CD8αα expression (E8I−/− mice). However, the precise contribution of CD8αα to sustained IL-7Rα expression and other memory CD8 T cell-associated changes has not been investigated. We found that IL-7Rα expression and generation of memory CD8 T cells that protect against secondary viral infection was considerably normal in E8I−/− animals. Interestingly, virus-specific CD4 T cell responses were elevated, and the relative surface levels of CD8αβ in activated T cells were reduced in E8I−/− mice compared with wild-type animals. Our results indicate that memory CD8 T cell development can occur independently of CD8αα.
CD4-Dependent Signaling Is Required for a Late Checkpoint during Th2 Development Associated with Resistance to Activation-Induced Cell Death
Authors: Tatari-Calderone Zohreh , Brogdon Jennifer L. , Tinsley Kevin W. , Ramezani Anahita , Leitenberg David 
Published: April 2014

Abstract
Previous studies have found that class II-restricted T cells from CD4-deficient mice reconstituted with a tail-less CD4 transgene have a specific defect in the development of Th2 effector cells; however, the reason for this defect was not clear. Following stimulation with a high potency peptide and exogenous IL-4, CD4-dependent signaling is required for optimal generation of a Th2 effector population. However, initial IL-4 and GATA-3 transcription is appropriately induced, suggesting that the initial stages of Th2 development are intact and independent of CD4 after priming with a strong agonist peptide. In addition to the defect in Th2 development, CD4 mutant T cells are also relatively resistant to activation-induced cell death (AICD). Furthermore, inhibition of AICD in wild-type T cells causes a defect in Th2 development similar to that seen in the CD4 mutant T cells. These data support the hypothesis that CD4-dependent signaling pathways regulate a distinct checkpoint in the expansion and commitment phase of Th2 development, which is related to dysregulation of AICD.