bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oncostatin M Receptor-β Signaling Limits Monocytic Cell Recruitment in Acute Inflammation
Authors: Hams Emily , Colmont Chantal S. , Dioszeghy Vincent , Hammond Victoria J. , Fielding Ceri A. , Williams Anwen S. , Tanaka Minoru , Miyajima Atsushi , Taylor Philip R. , Topley Nicholas , Jones Simon A. 
Published: April 2014

Abstract
Although the IL-6-related cytokine oncostatin M (OSM) affects processes associated with disease progression, the specific function of OSM in the face of an inflammatory challenge remains unclear. In this report, a peritoneal model of acute inflammation was used to define the influence of OSM on chemokine-mediated leukocyte recruitment. When compared with wild-type and IL-6-deficient mice, peritoneal inflammation in oncostatin M receptor-β-deficient (OSMR-KO) mice resulted in enhanced monocytic cell trafficking. In contrast to IL-6-deficient mice, OSMR-KO mice displayed no difference in neutrophil and lymphocyte migration. Subsequent in vitro studies using human peritoneal mesothelial cells and an in vivo appraisal of inflammatory chemokine expression after peritoneal inflammation identified OSM as a prominent regulator of CCL5 expression. Specifically, OSM inhibited IL-1β-mediated NF-κB activity and CCL5 expression in human mesothelial cells. This was substantiated in vivo where peritoneal inflammation in OSMR-KO mice resulted in a temporal increase in both CCL5 secretion and NF-κB activation. These findings suggest that IL-6 and OSM individually affect the profile of leukocyte trafficking, and they point to a hitherto unidentified interplay between OSM signaling and the inflammatory activation of NF-κB.
The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells
Authors: Hervé Roxane , Schmitz Thomas , Evain-Brion Danièle , Cabrol Dominique , Leroy Marie-Josèphe , Méhats Céline 
Published: April 2014

Abstract
Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF-α when stimulated by LPS. The transcription factor NF-κB is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-α. LPS induces the nuclear translocation of the NF-κB p65 subunit and the activation of three different NF-κB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-α production and the activation of the three NF-κB complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.
The Epithelial Anion Transporter Pendrin Is Induced by Allergy and Rhinovirus Infection, Regulates Airway Surface Liquid, and Increases Airway Reactivity and Inflammation in an Asthma Model
Authors: Nakagami Yasuhiro , Favoreto Silvio , Zhen Guohua , Park Sung-Woo , Nguyenvu Louis T. , Kuperman Douglas A. , Dolganov Gregory M. , Huang Xiaozhu , Boushey Homer A. , Avila Pedro C. , Erle David J. 
Published: April 2014

Abstract
Asthma exacerbations can be triggered by viral infections or allergens. The Th2 cytokines IL-13 and IL-4 are produced during allergic responses and cause increases in airway epithelial cell mucus and electrolyte and water secretion into the airway surface liquid (ASL). Since ASL dehydration can cause airway inflammation and obstruction, ion transporters could play a role in pathogenesis of asthma exacerbations. We previously reported that expression of the epithelial cell anion transporter pendrin is markedly increased in response to IL-13. Herein we show that pendrin plays a role in allergic airway disease and in regulation of ASL thickness. Pendrin-deficient mice had less allergen-induced airway hyperreactivity and inflammation than did control mice, although other aspects of the Th2 response were preserved. In cultures of IL-13-stimulated mouse tracheal epithelial cells, pendrin deficiency caused an increase in ASL thickness, suggesting that reductions in allergen-induced hyperreactivity and inflammation in pendrin-deficient mice result from improved ASL hydration. To determine whether pendrin might also play a role in virus-induced exacerbations of asthma, we measured pendrin mRNA expression in human subjects with naturally occurring common colds caused by rhinovirus and found a 4.9-fold increase in mean expression during colds. Studies of cultured human bronchial epithelial cells indicated that this increase could be explained by the combined effects of rhinovirus and IFN-γ, a Th1 cytokine induced during virus infection. We conclude that pendrin regulates ASL thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens.
Human Anti-Inflammatory Macrophages Induce Foxp3+GITR+CD25+ Regulatory T Cells, Which Suppress via Membrane-Bound TGFβ-1
Authors: Savage Nigel D. L. , de Boer Tjitske , Walburg Kimberley V. , Joosten Simone A. , van Meijgaarden Krista , Geluk Annemiek , Ottenhoff Tom H. M. 
Published: April 2014

Abstract
CD4+ T cell differentiation and function are critically dependent on the type of APC and the microenvironment in which Ag presentation occurs. Most studies have documented the effect of dendritic cells on effector and regulatory T cell differentiation; however, macrophages are the most abundant APCs in the periphery and can be found in virtually all organs and tissues. The effect of macrophages, and in particular their subsets, on T cell function has received little attention. Previously, we described distinct subsets of human macrophages (pro- and anti-inflammatory, mφ1 and mφ2, respectively) with highly divergent cell surface Ag expression and cytokine/chemokine production. We reported that human mφ1 promote, whereas mφ2 decrease, Th1 activation. Here, we demonstrate that mφ2, but not mφ1, induce regulatory T cells with a strong suppressive phenotype (Tmφ2). Their mechanism of suppression is cell-cell contact dependent, mediated by membrane-bound TGFβ-1 expressed on the regulatory T cell (Treg) population since inhibition of TGFβ-1 signaling in target cells blocks the regulatory phenotype. Tmφ2, in addition to mediating cell-cell contact-dependent suppression, express typical Treg markers such as CD25, glucocorticoid-induced TNF receptor (GITR), and Foxp3 and are actively induced by mφ2 from CD25-depleted cells. These data identify mφ2 cells as a novel APC subset capable of inducing Tregs. The ability of anti-inflammatory macrophages to induce Tregs in the periphery has important implications for understanding Treg dynamics in pathological conditions where macrophages play a key role in inflammatory disease control and exacerbation.
CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells
Authors: Guo Fei , Iclozan Cristina , Suh Woong-Kyung , Anasetti Claudio , Yu Xue-Zhong 
Published: April 2014

Abstract
CD28 is required for the development of regulatory T cells (Tregs; CD4+CD25+Foxp3+) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using wild-type, CD28-, ICOS-, or CD28/ICOS-double knockout mice on C57BL/6 background as T cell sources, we found that CD28 is essential, whereas ICOS is dispensable, for the development and homeostasis of Tregs. Furthermore, the differentiation of Tregs from naive CD4+CD25− T cells in vivo also depends on CD28. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb-blocked Treg differentiation from wild-type CD4+CD25− T cells and addition of IL-2 restored Treg differentiation from CD28−/− T cells. Other common γ-chain cytokines, IL-4, IL-7, or IL-15, do not share such a role with IL-2. Although CD28 is required for the differentiation of Tregs from naive T cells, already generated Tregs do not depend on CD28 to exert their suppressive function. Our study reveals a new aspect of CD28 function in regulating T cell response.
The RON Receptor Tyrosine Kinase Regulates IFN-γ Production and Responses in Innate Immunity
Authors: Wilson Caleph B. , Ray Manujendra , Lutz Michael , Sharda Daniel , Xu Jie , Hankey Pamela A. 
Published: April 2014

Abstract
Receptor tyrosine kinases are emerging as a class of key regulators of innate immune responses. We have shown previously that the RON receptor tyrosine kinases (murine Stk), expressed on tissue-resident macrophages, inhibit classical macrophage activation while promoting hallmarks of alternative activation, thus regulating the critical balance between the inflammatory and wound-healing properties of activated macrophages. We have also shown previously that RON−/− mice are more susceptible to in vivo endotoxin challenge than wild-type mice, suggesting that the expression of this receptor confers a degree of endotoxin resistance to these animals. Here we demonstrate that, in response to in vivo LPS challenge, RON−/− mice harbor significantly increased systemic levels of IFN-γ and IL-12p70 and increased levels of IL-12p40 transcript in their spleen. This elevation of IFN-γ can be attributed to splenic NK cells responding to the elevated levels of IL-12. Analysis of RON and IFN-γ receptor double-knockout mice indicates that the enhanced susceptibility of RON−/− mice to endotoxin challenge is dependent on IFN-γ-mediated signals. In vitro studies demonstrate that stimulation of primary peritoneal macrophages with macrophage-stimulating protein, the ligand for RON, inhibits IFN-γ-induced STAT1 phosphorylation and CIITA expression, resulting in reduced surface levels of MHC class II. Further studies demonstrating the induction of suppressor of cytokine signaling 1 via macrophage-stimulating protein/RON signaling provide a potential mechanistic insight into this regulatory pathway. These results indicate that the RON receptor regulates both the production of and response to IFN-γ, resulting in enhanced susceptibility to endotoxin challenge.
Cooperative Regulation of Non-Small Cell Lung Carcinoma Angiogenic Potential by Macrophage Migration Inhibitory Factor and Its Homolog, d-Dopachrome Tautomerase
Authors: Coleman Arlixer M. , Rendon Beatriz E. , Zhao Ming , Qian Ming-Wei , Bucala Richard , Xin Dan , Mitchell Robert A. 
Published: April 2014

Abstract
Tumor-derived growth factors and cytokines stimulate neoangiogenesis from surrounding capillaries to support tumor growth. Recent studies have revealed that macrophage migration inhibitory factor (MIF) expression is increased in lung cancer, particularly non-small cell lung carcinomas (NSCLC). Because MIF has important autocrine effects on normal and transformed cells, we investigated whether autocrine MIF and its only known family member, d-dopachrome tautomerase (D-DT), promote the expression of proangiogenic factors CXCL8 and vascular endothelial growth factor in NSCLC cells. Our results demonstrate that the expression of CXCL8 and vascular endothelial growth factor are strongly reliant upon both the individual and cooperative activities of the two family members. CXCL8 transcriptional regulation by MIF and D-DT appears to involve a signaling pathway that includes the activation of JNK, c-jun phosphorylation, and subsequent AP-1 transcription factor activity. Importantly, HUVEC migration and tube formation induced by supernatants from lung adenocarcinoma cells lacking either or both MIF and D-DT are substantially reduced when compared with normal supernatants. Finally, we demonstrate that the cognate MIF receptor, CD74, is necessary for both MIF- and D-DT-induced JNK activation and CXCL8 expression, suggesting its potential involvement in angiogenic growth factor expression. This is the first demonstration of a biological role for D-DT, and its synergism with MIF suggests that the combined therapeutic targeting of both family members may enhance current anti-MIF-based therapies.
Mucosally Delivered Dendritic Cells Activate T Cells Independently of IL-12 and Endogenous APCs
Authors: McCormick Sarah , Santosuosso Michael , Small Cherrie-Lee , Shaler Christopher R. , Zhang Xizhong , Jeyanathan Mangalakumari , Mu Jingyu , Takenaka Shunsuke , Ngai Patricia , Gauldie Jack , Wan Yonghong , Xing Zhou 
Published: April 2014

AbstractIn vitro manipulated dendritic cells (DC) have increasingly been used as a promising vaccine formulation against cancer and infectious disease. However, improved understanding of the immune mechanisms is needed for the development of safe and efficacious mucosal DC immunization. We have developed a murine model of respiratory mucosal immunization by using a genetically manipulated DC vaccine. Within 24 h of intranasal delivery, the majority of vaccine DCs migrated to the lung mucosa and draining lymph nodes and elicited a significant level of T cells capable of IFN-γ secretion and CTL in the airway lumen as well as substantial T cell responses in the spleen. And such T cell responses were associated with enhanced protection against respiratory mucosal intracellular bacterial challenge. In comparison, parenteral i.m. DC immunization did not elicit marked airway luminal T cell responses and immune protection regardless of strong systemic T cell activation. Although repeated mucosal DC delivery boosted Ag-specific T cells in the airway lumen, added benefits to CD8 T cell activation and immune protection were not observed. By using MHC-deficient vaccine DCs, we further demonstrated that mucosal DC immunization-mediated CD8 and CD4 T cell activation does not require endogenous DCs. By using IL-12-deficient vaccine DCs, we also observed that IL-12−/− DCs failed to migrate to the lymph nodes but remained capable of T cell activation. Our observations indicate that mucosal delivery of vaccine DCs represents an effective approach to enhance mucosal T cell immunity, which may operate independent of vaccine IL-12 and endogenous DCs.
Leukocyte Extravasation: An Immunoregulatory Role for α-l-Fucosidase?
Authors: Ali Simi , Jenkins Yvonne , Kirkley Maureen , Dagkalis Athanasios , Manivannan Ayyakkannu , Crane Isabel Joan , Kirby John A. 
Published: April 2014

Abstract
Fucosylated oligosaccharides and glycoconjugates have been implicated in several biological events, including the cell-cell adhesion processes that mediate inflammation. α-l-Fucosidase (ALF) is an exoglycosidase that is involved in the hydrolytic degradation of α-l-fucose from glycoconjugates. In this study, we investigated the potential role of ALF in regulation of leukocyte migration. Measurement of transendothelial migration in response to CCL5 demonstrated that pretreatment of monocytic cells with ALF reduced migration (p = 0.0004) to a greater extent than treatment of the endothelial monolayer (p = 0.0374). Treatment with ALF significantly reduced the adhesion of monocytic cells to immobilized P-selectin.Fc. A murine model of experimental autoimmune uveitis was then used to show that treatment of splenic cells with ALF produced an 8.6-fold decrease in rolling and a 3.2-fold decrease in cell migration across the retinal vasculature. Further in vitro studies demonstrated that treatment of monocytes with the chemokines CCL3 or CCL5 increased the level of mRNA encoding ALF; this was accompanied by the detection of significant increases in both the 51- and 56-kDa components of ALF by Western blotting. Treatment of monocytic cells with ALF for 2 h significantly reduced the cell surface expression of CD31, with a further decrease in expression observed after 5 h (p = 0.002). Thus, CD31 and fucosylated ligands of P-selectin seem to be the candidates through which ALF mediates its effect in vitro. These data identify a previously unrecognized immunoregulatory role for ALF in late stages of inflammation.
Binding of C/EBPβ to the C-Reactive Protein (CRP) Promoter in Hep3B Cells Is Associated with Transcription of CRP mRNA
Authors: Young Duprane Pedaci , Kushner Irving , Samols David 
Published: April 2014

Abstract
Expression of the acute phase protein C-reactive protein (CRP) is tightly regulated in hepatocytes. Although very little CRP mRNA is transcribed normally, inflammatory stimuli are followed by a dramatic increase in mRNA synthesis and accumulation. IL-6 and IL-1β are believed to be the major cytokines responsible for induction of CRP and other acute phase proteins. Our previous studies, using transient transfection and EMSA experiments, implicated involvement of the transcription factors C/EBPβ, STAT3, Rel p50, and c-Rel in CRP induction. In the current study we used chromatin immunoprecipitation assays to determine the kinetics of transcription factor occupancy of these transcription factors on the endogenous CRP promoter. All of these transcription factors were found bound to the endogenous CRP promoter in the absence of cytokines, but cytokine treatment markedly increased binding of only C/EBPβ. In addition, c-Rel and TATA box-binding protein (TBP) appeared to occupy the promoter in parallel in the presence of cytokines. In the absence of cytokines, CRP mRNA accumulation was not measurable but began to increase by 3 h after exposure of cells to IL-1β plus IL-6, peaking at 12 h with secondary peaks at 18 and 24 h. The secondary peaks in mRNA expression paralleled the pattern of binding of c-Rel and TBP to the CRP promoter. We conclude that the CRP promoter has a low level of transcription factor occupancy in the absence of cytokines and induction occurs with binding of C/EBP, and that c-Rel and TBP are important for modulating CRP expression.
Antigen Specificity Acquisition of Adoptive CD4+ Regulatory T Cells via Acquired Peptide-MHC Class I Complexes
Authors: Hao Siguo , Yuan Jinying , Xu Shulin , Munegowda Manjunatha Ankathatti , Deng Yulin , Gordon John , Xing Zhou , Xiang Jim 
Published: April 2014

Abstract
The Ag-specific CD4+ regulatory T (Tr) cells play an important role in immune suppression in autoimmune diseases and antitumor immunity. However, the molecular mechanism for Ag-specificity acquisition of adoptive CD4+ Tr cells is unclear. In this study, we generated IL-10- and IFN-γ-expressing type 1 CD4+ Tr (Tr1) cells by stimulation of transgenic OT II mouse-derived naive CD4+ T cells with IL-10-expressing adenovirus (AdVIL-10)-transfected and OVA-pulsed dendritic cells (DCOVA/IL-10). We demonstrated that both in vitro and in vivo DCOVA/IL-10-stimulated CD4+ Tr1 cells acquired OVA peptide MHC class (pMHC) I which targets CD4+ Tr1 cells suppressive effect via an IL-10-mediated mechanism onto CD8+ T cells, leading to an enhanced suppression of DCOVA-induced CD8+ T cell responses and antitumor immunity against OVA-expressing murine B16 melanoma cells by ≈700% relative to analogous CD4+ Tr1 cells without acquired pMHC I. Interestingly, the nonspecific CD4+25+ Tr cells can also become OVA Ag specific and more immunosuppressive in inhibition of OVA-specific CD8+ T cell responses and antitumor immunity after uptake of DCOVA-released exosomal pMHC I complexes. Taken together, the Ag-specificity acquisition of CD4+ Tr cells via acquiring DC’s pMHC I may be an important mean in augmenting CD4+ Tr cell suppression.
Ligand-Dependent Induction of Noninflammatory Dendritic Cells by Anergic Invariant NKT Cells Minimizes Autoimmune Inflammation
Authors: Wang Jianxiong , Cho Suzanne , Ueno Aito , Cheng Lu , Xu Bo-You , Desrosiers Melanie D. , Shi Yan , Yang Yang 
Published: April 2014

Abstract
Stimulated by an agonistic ligand, α-galactosylceramide (αGalCer), invariant NKT (iNKT) cells are capable of both eliciting antitumor responses and suppressing autoimmunity, while they become anergic after an initial phase of activation. It is unknown how iNKT cells act as either activators or regulators in different settings of cellular immunity. We examined effects of αGalCer administration on autoimmune inflammation and characterized phenotypes and functional status of iNKT cells and dendritic cells in αGalCer-treated NOD mice. Although iNKT cells became and remained anergic after the initial exposure to their ligand, anergic iNKT cells induce noninflammatory DCs in response to αGalCer restimulation, whereas activated iNKT cells induce immunogenic maturation of DCs in a small time window after the priming. Induction of noninflammatory DCs results in the activation and expansion of islet-specific T cells with diminished proinflammatory cytokine production. The noninflammatory DCs function at inflammation sites in an Ag-specific fashion, and the persistence of noninflammatory DCs critically inhibits autoimmune pathogenesis in NOD mice. Anergic differentiation is a regulatory event that enables iNKT cells to transform from promoters to suppressors, down-regulating the ongoing inflammatory responses, similar to other regulatory T cells, through a ligand-dependent mechanism.
IFN-γ-Producing Human Invariant NKT Cells Promote Tumor-Associated Antigen-Specific Cytotoxic T Cell Responses
Authors: Moreno María , Molling Johan W. , von Mensdorff-Pouilly Silvia , Verheijen René H. M. , Hooijberg Erik , Kramer Duco , Reurs Anneke W. , van den Eertwegh Alfons J. M. , von Blomberg B. Mary E. , Scheper Rik J. , Bontkes Hetty J. 
Published: April 2014

Abstract
CD1d-restricted invariant NKT (iNKT) cells can enhance immunity to cancer or prevent autoimmunity, depending on the cytokine profile secreted. Antitumor effects of the iNKT cell ligand α-galactosylceramide (αGC) and iNKT cell adoptive transfer have been demonstrated in various tumor models. Together with reduced numbers of iNKT cells in cancer patients, which have been linked to poor clinical outcome, these data suggest that cancer patients may benefit from therapy aiming at iNKT cell proliferation and activation. Herein we present results of investigations on the effects of human iNKT cells on Ag-specific CTL responses. iNKT cells were expanded using αGC-pulsed allogeneic DC derived from the acute myeloid leukemia cell line MUTZ-3, transduced with CD1d to enhance iNKT cell stimulation, and with IL-12 to stimulate type 1 cytokine production. Enhanced activation and increased IFN-γ production was observed in iNKT cells, irrespective of CD4 expression, upon stimulation with IL-12-overexpressing dendritic cells. IL-12-stimulated iNKT cells strongly enhanced the MART-1 (melanoma Ag recognized by T cell 1)-specific CD8+ CTL response, which was dependent on iNKT cell-derived IFN-γ. Furthermore, autologous IL-12-overexpressing dendritic cells, loaded with Ag as well as αGC, was superior in stimulating both iNKT cells and Ag-specific CTL. This study shows that IL-12-overexpressing allogeneic dendritic cells expand IFN-γ-producing iNKT cells, which may be more effective against tumors in vivo. Furthermore, the efficacy of autologous Ag-loaded DC vaccines may well be enhanced by IL-12 overexpression and loading with αGC.