bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-8 Is a Key Chemokine Regulating Neutrophil Recruitment in a New Mouse Model ofShigella-Induced Colitis
Authors: Singer Monique , Sansonetti Philippe J. 
Published: April 2014

AbstractThe lack of a mouse model of acute rectocolitis mimicking human bacillary dysentery in the presence of invasive Shigella is a major handicap to study the pathogenesis of the disease and to develop a Shigella vaccine. The inability of the mouse intestinal mucosa to elicit an inflammatory infiltrate composed primarily of polymorphonuclear leukocytes (PMN) may be due to a defect in epithelial invasion, in the sensing of invading bacteria, or in the effector mechanisms that recruit the PMN infiltrate. We demonstrate that the BALB/cJ mouse colonic epithelium not only can be invaded by Shigella, but also elicits an inflammatory infiltrate that, however, lacks PMN. This observation points to a major defect of mice in effector mechanisms, particularly the lack of expression of the CXC chemokine, IL-8. Indeed, this work demonstrates that the delivery of recombinant human IL-8, together with Shigella infection of the colonic epithelial surface, causes an acute colitis characterized by a strong PMN infiltrate that, by all criteria, including transcription profiles of key mediators of the innate/inflammatory response and histopathological lesions, mimics bacillary dysentery. This is a major step forward in the development of a murine model of bacillary dysentery.
Andrographolide Attenuates Inflammation by Inhibition of NF-κB Activation through Covalent Modification of Reduced Cysteine 62 of p50
Authors: Xia Yi-Feng , Ye Bu-Qing , Li Yi-Dan , Wang Jian-Guo , He Xiang-Jiu , Lin Xianfeng , Yao Xinsheng , Ma Dawei , Slungaard Arne , Hebbel Robert P. , Key Nigel S. , Geng Jian-Guo 
Published: April 2014

Abstract
NF-κB is a central transcriptional factor and a pleiotropic regulator of many genes involved in immunological responses. During the screening of a plant extract library of traditional Chinese herbal medicines, we found that NF-κB activity was potently inhibited by andrographolide (Andro), an abundant component of the plant Andrographis that has been commonly used as a folk remedy for alleviation of inflammatory disorders in Asia for millennia. Mechanistically, it formed a covalent adduct with reduced cysteine (62) of p50, thus blocking the binding of NF-κB oligonucleotide to nuclear proteins. Andro suppressed the activation of NF-κB in stimulated endothelial cells, which reduced the expression of cell adhesion molecule E-selectin and prevented E-selectin-mediated leukocyte adhesion under flow. It also abrogated the cytokine- and endotoxin-induced peritoneal deposition of neutrophils, attenuated septic shock, and prevented allergic lung inflammation in vivo. Notably, it had no suppressive effect on IκBα degradation, p50 and p65 nuclear translocation, or cell growth rates. Our results thus reveal a unique pharmacological mechanism of Andro’s protective anti-inflammatory actions.
CD137-Deficient Mice Have Reduced NK/NKT Cell Numbers and Function, Are Resistant to Lipopolysaccharide-Induced Shock Syndromes, and Have Lower IL-4 Responses
Authors: Vinay Dass S. , Choi Beom K. , Bae Jun S. , Kim Won Y. , Gebhardt Bryan M. , Kwon Byoung S. 
Published: April 2014

AbstractCD137, a member of the TNF superfamily, is involved in T cell and NK cell activation and cytokine production. To establish its in vivo role in systems dependent on NK and NKT cells, we studied the response of CD137−/− mice to LPS-induced shock, tumor killing, and their IL-4-controlled Th2 responses. In both high and low dose shock models, all the CD137-deficient mice, but none of the wild-type BALB/c mice, survived. After injection of LPS/2-amino-2-deoxy-d-galactose (D-gal), CD137−/− mice had reduced serum cytokine levels and substantially impaired liver IFN-γ and TNF-α mRNA levels. Phenotypic analysis of mononuclear cells revealed fewer NK and NKT cells in the CD137−/− mice. The knockout mice did not generate a rapid IL-4 response after systemic T cell activation, or effective Ag-specific Th2 responses. In addition, both in vitro and in vivo NK-specific cytolytic activities were reduced. These findings suggest that CD137-directed NK/NKT cells play an important role in the inflammatory response leading to the production of proinflammatory cytokines, LPS-induced septic shock, and tumor killing, as well as IL-4-dependent Th2 responses.
Accelerated Ischemia/Reperfusion-Induced Injury in Autoimmunity-Prone Mice
Authors: Fleming Sherry D. , Monestier Marc , Tsokos George C. 
Published: April 2014

AbstractNatural Abs have been implicated in initiating mesenteric ischemia/reperfusion (I/R)-induced tissue injury. Autoantibodies have affinity and self-Ag recognition patterns similar to natural Abs. We considered that autoimmunity-prone mice that express high titers of autoantibodies should have enhanced I/R-induced injury. Five-month-old B6.MRL/lpr mice displayed accelerated and enhanced intestinal I/R-induced damage compared with 2-mo-old B6.MRL/lpr and age-matched C57BL/6 mice. Similarly, older autoimmune mice had accelerated remote organ (lung) damage. Infusion of serum IgG derived from 5-mo-old but not 2-mo-old B6.MRL/lpr into I/R resistant Rag-1−/− mice rendered them susceptible to local and remote organ injury. Injection of monoclonal IgG anti-DNA and anti-histone Abs into Rag-1−/− mice effectively reconstituted tissue injury. These data show that like natural Abs, autoantibodies, such as anti-dsDNA and anti-histone Abs, can instigate I/R injury and suggest that they are involved in the development of tissue damage in patients with systemic lupus erythematosus.
Complement Mediates the Binding of HIV to Erythrocytes
Authors: Horakova Eliska , Gasser Olivier , Sadallah Salima , Inal Jameel M. , Bourgeois Guillaume , Ziekau Ingrid , Klimkait Thomas , Schifferli Jürg A. 
Published: April 2014

AbstractA fraction of HIV is associated with erythrocytes even when the virus becomes undetectable in plasma under antiretroviral therapy. The aim of the present work was to further characterize this association in vitro. We developed an in vitro model to study the factors involved in the adherence of HIV-1 to erythrocytes. Radiolabeled HIV-1 (HIV) and preformed HIV-1/anti-HIV immune complexes (HIV-IC) were opsonized in various human sera, purified using sucrose density gradient ultracentrifugation, and incubated with human erythrocytes. We observed that, when opsonized in normal human serum, not only HIV-IC, but also HIV, bound to erythrocytes, although the adherence of HIV was lower than that of HIV-IC. The adherence was abolished when the complement system was blocked, but was maintained in hypogammaglobulinemic sera. Complement-deficient sera indicated that both pathways of complement were important for optimal adherence. No adherence was seen in C1q-deficient serum, and the adherence of HIV was reduced when the alternative pathway was blocked using anti-factor D Abs. The adherence could be inhibited by an mAb against complement receptor 1. At supraphysiological concentrations, purified C1q mediated the binding of a small fraction of HIV and HIV-IC to erythrocytes. In conclusion, HIV-IC bound to erythrocytes as other types of IC do when exposed to complement. Of particular interest was that HIV alone bound also to erythrocytes in a complement/complement receptor 1-dependent manner. Thus, erythrocytes may not only deliver HIV-IC to organs susceptible to infection, but free HIV as well. This may play a crucial role in the progression of the primary infection.
Enhanced Tumor-Specific Long-Term Immunity of Hemaggluttinating Virus of Japan-Mediated Dendritic Cell-Tumor Fused Cell Vaccination by Coadministration with CpG Oligodeoxynucleotides
Authors: Hiraoka Kazuya , Yamamoto Seiji , Otsuru Satoru , Nakai Seiji , Tamai Katsuto , Morishita Ryuichi , Ogihara Toshio , Kaneda Yasufumi 
Published: April 2014

Abstract
Immunization with dendritic cells (DCs) using various Ag-loading approaches has shown promising results in tumor-specific immunotherapy and immunoprevention. Fused cells (FCs) that are generated from DCs and tumor cells are one of effective cancer vaccines because both known and unknown tumor Ags are presented on the FCs and recognized by T cells. In this study, we attempted to augment antitumor immunity by the combination of DC-tumor FC vaccination with immunostimulatory oligodeoxynucleotides containing CpG motif (CpG ODN). Murine DCs were fused with syngeneic tumor cells ex vivo using inactivated hemagglutinating virus of Japan (Sendai virus). Mice were intradermally (i.d.) immunized with FCs and/or CpG ODN. Coadministration of CpG ODN enhanced the phenotypical maturation of FCs and unfused DCs, and the production of Th1 cytokines, such as IFN-γ and IL-12, leading to the induction of tumor-specific CTLs without falling into T cell anergy. In addition, immunization with FCs + CpG ODN provided significant protection against lethal s.c. tumor challenge and spontaneous lung metastasis compared with that with either FCs or CpG ODN alone. Furthermore, among mice that rejected tumor challenge, the mice immunized with FCs + CpG ODN, but not the mice immunized with FCs or CpG ODN alone, completely rejected tumor rechallenge, indicating that CpG ODN provided long-term maintenance of tumor-specific immunity induced by FCs. Thus, the combination of DC-tumor FCs and CpG ODN is an effective and feasible cancer vaccine to prevent the generation and recurrence of cancers.
Intestinal Epithelial Antigen Induces Mucosal CD8 T Cell Tolerance, Activation, and Inflammatory Response
Authors: Liu Zhanju , Lefrançois Leo 
Published: April 2014

Abstract
Intestinal autoimmune diseases are thought to be associated with a breakdown in tolerance, leading to mucosal lymphocyte activation perhaps as a result of encounter with bacterium-derived Ag. To study mucosal CD8+ T cell activation, tolerance, and polarization of autoimmune reactivity to self-Ag, we developed a novel (Fabpl4× at −132-OVA) transgenic mouse model expressing a truncated form of OVA in intestinal epithelia of the terminal ileum and colon. We found that OVA-specific CD8+ T cells were partially tolerant to intestinal epithelium-derived OVA, because oral infection with Listeria monocytogenes-encoding OVA did not elicit an endogenous OVA-specific MHC class I tetramer+CD8+ T cell response and IFN-γ-, IL-4-, and IL-5-secreting T cells were decreased in the Peyer’s patches, mesenteric lymph nodes, and intestinal mucosa of transgenic mice. Adoptive transfer of OVA-specific CD8+ (OT-I) T cells resulted in their preferential expansion in the Peyer’s patches and mesenteric lymph nodes and subsequently in the epithelia and lamina propria but failed to cause mucosal inflammation. Thus, CFSE-labeled OT-I cells greatly proliferated in these tissues by 5 days posttransfer. Strikingly, OT-I cell-transferred Fabpl4× at −132-OVA transgenic mice underwent a transient weight loss and developed a CD8+ T cell-mediated acute enterocolitis 5 days after oral L. monocytogenes-encoding OVA infection. These findings indicate that intestinal epithelium-derived “self-Ag” gains access to the mucosal immune system, leading to Ag-specific T cell activation and clonal deletion. However, when Ag is presented in the context of bacterial infection, the associated inflammatory signals drive Ag-specific CD8+ T cells to mediate intestinal immunopathology.
Antisense Oligonucleotides Down-Regulating Costimulation Confer Diabetes-Preventive Properties to Nonobese Diabetic Mouse Dendritic Cells
Authors: Machen Jennifer , Harnaha Jo , Lakomy Robert , Styche Alexis , Trucco Massimo , Giannoukakis Nick 
Published: April 2014

AbstractPhenotypically “immature” dendritic cells (DCs), defined by low cell surface CD40, CD80, and CD86 can elicit host immune suppression in allotransplantation and autoimmunity. Herein, we report the most direct means of achieving phenotypic immaturity in NOD bone marrow-derived DCs aiming at preventing diabetes in syngeneic recipients. CD40, CD80, and CD86 cell surface molecules were specifically down-regulated by treating NOD DCs ex vivo with a mixture of antisense oligonucleotides targeting the CD40, CD80, and CD86 primary transcripts. The incidence of diabetes was significantly delayed by a single injection of the engineered NOD DCs into syngeneic recipients. Insulitis was absent in diabetes-free recipients and their splenic T cells proliferated in response to alloantigen. Engineered DC promoted an increased prevalence of CD4+CD25+ T cells in NOD recipients at all ages examined and diabetes-free recipients exhibited significantly greater numbers of CD4+CD25+ T cells compared with untreated NOD mice. In NOD-scid recipients, antisense-treated NOD DC promoted an increased prevalence of these putative regulatory T cells. Collectively, these data demonstrate that direct interference of cell surface expression of the major costimulatory molecules at the transcriptional level confers diabetes protection by promoting, in part, the proliferation and/or survival of regulatory T cells. This approach is a useful tool by which DC-mediated activation of regulatory T cells can be studied as well as a potential therapeutic option for type 1 diabetes.
Bone Marrow Precursors of Nonobese Diabetic Mice Develop into Defective Macrophage-Like Dendritic Cells In Vitro
Authors: Nikolic Tatjana , Bunk Marjolijn , Drexhage Hemmo A. , Leenen Pieter J. M. 
Published: April 2014

Abstract
The NOD mouse spontaneously develops autoimmune diabetes. Dendritic cells (DC) play a crucial role in the autoimmune response. Previous studies have reported a defective DC generation in vitro from the NOD mouse bone marrow (BM), but a deviated development of myeloid precursors into non-DC in response to GM-CSF was not considered. In this study, we demonstrate several abnormalities during myeloid differentiation of NOD BM precursors using GM-CSF in vitro. 1) We found reduced proliferation and increased cell death in NOD cultures, which explain the previously reported low yield of DC progeny in NOD. Cell yield in NOR cultures was normal. 2) In a detailed analysis GM-CSF-stimulated cultures, we observed in both NOD and NOR mice an increased frequency of macrophages, identified as CD11c+/MHCII− cells with typical macrophage morphology, phenotype, and acid phosphatase activity. This points to a preferential maturation of BM precursors into macrophages in mice with the NOD background. 3) The few CD11c+/MHCIIhigh cells that we obtained from NOD and NOR cultures, which resembled prototypic mature DC, appeared to be defective in stimulating allogeneic T cells. These DC had also strong acid phosphatase activity and elevated expression of monocyte/macrophage markers. In conclusion, in this study we describe a deviated development of myeloid BM precursors of NOD and NOR mice into macrophages and macrophage-like DC in vitro. Potentially, these anomalies contribute to the dysfunctional regulation of tolerance in NOD mice yet are insufficient to induce autoimmune diabetes because they occurred partly in NOR mice.
Melanoma Differentiation-Associated Gene-7/IL-24 Gene Enhances NF-κB Activation and Suppresses Apoptosis Induced by TNF
Authors: Aggarwal Sita , Takada Yasunari , Mhashilkar Abner M. , Sieger Kerry , Chada Sunil , Aggarwal Bharat B. 
Published: April 2014

Abstract
Melanoma differentiation-associated gene-7 (mda-7), also referred to as IL-24, is a novel growth regulatory cytokine that has been shown to regulate the immune system by inducing the expression of inflammatory cytokines, such as TNF, IL-1, and IL-6. Whether the induction of these cytokines by MDA-7 is mediated through activation of NF-κB or whether it regulates cytokine signaling is not known. In the present report we investigated the effect of MDA-7 on NF-κB activation and on TNF-induced NF-κB activation and apoptosis in human embryonic kidney 293 cells. Stable or transient transfection with mda-7 into 293 cells failed to activate NF-κB. However, TNF-induced NF-κB activation was significantly enhanced in mda-7-transfected cells, as indicated by DNA binding, p65 translocation, and NF-κB-dependent reporter gene expression. Mda-7 transfection also potentiated NF-κB reporter activation induced by TNF receptor-associated death domain and TNF receptor-associated factor-2. Cytoplasmic MDA-7 with deleted signal sequence was as effective as full-length MDA-7 in potentiating TNF-induced NF-κB reporter activity. Secretion of MDA-7 was not required for the potentiation of TNF-induced NF-κB activation. TNF-induced expression of the NF-κB-regulated gene products cyclin D1 and cyclooxygenase-2, were significantly up-regulated by stable expression of MDA-7. Furthermore, MDA-7 expression abolished TNF-induced apoptosis, and suppression of NF-κB by IκBα kinase inhibitors enhanced apoptosis. Overall, our results indicate that stable or transient MDA-7 expression alone does not substantially activate NF-κB, but potentiates TNF-induced NF-κB activation and NF-κB-regulated gene expression. Potentiation of NF-κB survival signaling by MDA-7 inhibits TNF-mediated apoptosis.
Direct Antigen Presentation by a Xenograft Induces Immunity Independently of Secondary Lymphoid Organs
Authors: Tesar Bethany M. , Chalasani Geetha , Smith-Diggs Lonnette , Baddoura Fady K. , Lakkis Fadi G. , Goldstein Daniel R. 
Published: April 2014

Abstract
The location of immune activation is controversial during acute allograft rejection and unknown in xenotransplantation. To determine where immune activation to a xenograft occurs, we examined whether splenectomized alymphoplastic mice that possess no secondary lymphoid organs can reject porcine skin xenografts. Our results show that these mice rejected their xenografts, in a T cell-dependent fashion, at the same tempo as wild-type recipients, demonstrating that xenograft rejection is not critically dependent on secondary lymphoid organs. Furthermore, we provide evidence that immune activation in the bone marrow did not take place during xenograft rejection. Importantly, immunity to xenoantigens was only induced after xenotransplantation and not by immunization with porcine spleen cells, as xenografted mutant mice developed an effector response, whereas mutant mice immunized by porcine spleen cells via i.p. injection failed to do so. Moreover, we provide evidence that antixenograft immunity occurred via direct and indirect Ag presentation, as recipient T cells could be stimulated by either donor spleen cells or recipient APCs. Thus, our data provide evidence that direct and indirect Ag presentation by a xenograft induces immunity in the absence of secondary lymphoid organs. These results have important implications for developing relevant xenotransplantation protocols.
bcl-xL Is Critical for Dendritic Cell Survival In Vivo
Authors: Hon Huiming , Rucker Edmund B. , Hennighausen Lothar , Jacob Joshy 
Published: April 2014

Abstract
Dendritic cells (DC) are important regulators of immune function, transporting Ags from the periphery to draining lymph nodes (dLN) where they prime Ag-specific T lymphocytes. The magnitude of the immune response generated depends upon the longevity of the Ag-bearing DC in lymphoid tissues. We hypothesized that the control of DC survival is regulated by the antiapoptotic factor bcl-xL. Gene gun immunization of dual-expression DNA vaccines into a bcl-xfl/fl mouse resulted in the delivery of Ag, as well as selective deletion of the bcl-x gene in directly transfected, skin-residing DC. bcl-x-deficient DC failed to mount effective immune responses, and this corresponded to their rapid disappearance from the dLN due to apoptosis. We confirmed these results using RNA interference to specifically silence the antiapoptotic bcl-xL isoform in targeted skin-residing DC of C57BL/6 mice. In addition, delivery of bcl-xL in trans complemented the bcl-x deficiency in DC of bcl-xfl/fl mice, resulting in the maintenance of normal levels of Ag-bearing DC in the dLN. Taken together, our work demonstrates that the bcl-xL isoform is critical for survival of skin-derived, Ag-bearing DC in vivo.
LFA-1 on CD4+ T Cells Is Required for Optimal Antigen-Dependent Activation In Vivo
Authors: Kandula Sravanthi , Abraham Clara 
Published: April 2014

AbstractThe leukocyte-specific integrin, LFA-1, plays a critical role in trafficking of T cells to both lymphoid and nonlymphoid tissues. However, the role of LFA-1 in T cell activation in vivo has been less well understood. Although there have been reports describing LFA-1-deficient T cell response defects in vivo, due to impaired migration to lymphoid structures and to sites of effector function in the absence of LFA-1, it has been difficult to assess whether T cells also have a specific activation defect in vivo. We examined the role of LFA-1 in CD4+ T cell activation in vivo by using a system that allows for segregation of the migration and activation defects through the adoptive transfer of LFA-1-deficient (CD18−/−) CD4+ T cells from DO11.10 Ag-specific TCR transgenic mice into wild-type BALB/c mice. We find that in addition to its role in trafficking to peripheral lymph nodes, LFA-1 is required for optimal CD4+ T cell priming in vivo upon s.c. immunization. CD18−/− DO11.10 CD4+ T cells primed in the lymph nodes demonstrate defects in IL-2 and IFN-γ production. In addition, recipient mice adoptively transferred with CD18−/− DO11.10 CD4+ T cells demonstrate a defect in OVA-specific IgG2a production after s.c. immunization. The defect in priming of CD18−/− CD4+ T cells persists even in the presence of proliferating CD18+/− CD4+ T cells and in lymphoid structures to which there is no migration defect. Taken together, these results demonstrate that LFA-1 is required for optimal CD4+ T cell priming in vivo.
Activation of Acid Sphingomyelinase and Its Inhibition by the Nitric Oxide/Cyclic Guanosine 3′,5′-Monophosphate Pathway: Key Events in Escherichia coli-Elicited Apoptosis of Dendritic Cells
Authors: Falcone Sestina , Perrotta Cristiana , De Palma Clara , Pisconti Addolorata , Sciorati Clara , Capobianco Annalisa , Rovere-Querini Patrizia , Manfredi Angelo A. , Clementi Emilio 
Published: April 2014

Abstract
Depletion of dendritic cells (DCs) via apoptosis contributes to sepsis-induced immune suppression. The mechanisms leading to DC apoptosis during sepsis are not known. In this study we report that immature DCs undergo apoptosis when treated with high numbers of Escherichia coli. This effect was mimicked by high concentrations of LPS. Apoptosis was accompanied by generation of ceramide through activation of acid sphingomyelinase (A-SMase), was prevented by inhibitors of this enzyme, and was restored by exogenous ceramide. Compared with immature DCs, mature DCs expressed significantly reduced levels of A-SMase, did not generate ceramide in response to E. coli or LPS, and were insensitive to E. coli- and LPS-triggered apoptosis. However, sensitivity to apoptosis was restored by addition of exogenous A-SMase or ceramide. Furthermore, inhibition of A-SMase activation and ceramide generation was found to be the mechanism through which the immune-modulating messenger NO protects immature DCs from the apoptogenic effects of E. coli and LPS. NO acted through formation of cGMP and stimulation of the cGMP-dependent protein kinase. The relevance of A-SMase and its inhibition by NO/cGMP were confirmed in a mouse model of LPS-induced sepsis. DC apoptosis was significantly higher in inducible NO synthase-deficient mice than in wild-type animals and was significantly reduced by treatment ex vivo with NO, cGMP, or the A-SMase inhibitor imipramine. Thus, A-SMase plays a central role in E. coli/LPS-induced DC apoptosis and its inhibition by NO, and it might be a target of new therapeutic approaches to sepsis.