bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholera Toxin B Pretreatment of Macrophages and Monocytes Diminishes Their Proinflammatory Responsiveness to Lipopolysaccharide
Authors: Burkart Volker , Kim Yoong-Eun , Hartmann Bettina , Ghiea Iona , Syldath Ulrike , Kauer Manfred , Fingberg Waltraud , Hanifi-Moghaddam Pejman , Müller Sylvia , Kolb Hubert 
Published: April 2014

AbstractThe cholera toxin B chain (CTB) has been reported to suppress T cell-dependent autoimmune diseases and to potentiate tolerance of the adaptive immune system. We have analyzed the effects of CTB on macrophages in vitro and have found that preincubation with CTB (10 μg/ml) suppresses the proinflammatory reaction to LPS challenge, as demonstrated by suppressed production of TNF-α, IL-6, IL-12(p70), and NO (p &lt; 0.01) in cells of macrophage lines. Pre-exposure to CTB also suppresses LPS-induced TNF-α and IL-12(p70) formation in human PBMC. Both native and recombinant CTB exhibited suppressive activity, which was shared by intact cholera toxin. In cells of the human monocyte line Mono Mac 6, exposure to CTB failed to suppress the production of IL-10 in response to LPS. Control experiments excluded a role of possible contamination of CTB by endotoxin or intact cholera toxin. The suppression of TNF-α production occurred at the level of mRNA formation. Tolerance induction by CTB was dose and time dependent. The suppression of TNF-α and IL-6 production could be counteracted by the addition of Abs to IL-10 and TGF-β. IFN-γ also antagonized the actions of CTB on macrophages. In contrast to desensitization by low doses of LPS, tolerance induction by CTB occurred silently, i.e., in the absence of a measurable proinflammatory response. These findings identify immune-deviating properties of CTB at the level of innate immune cells and may be relevant to the use of CTB in modulating immune-mediated diseases.
In Vivo Dehydroepiandrosterone Restores Age-Associated Defects in the Protein Kinase C Signal Transduction Pathway and Related Functional Responses
Authors: Corsini Emanuela , Lucchi Laura , Meroni Massimo , Racchi Marco , Solerte Bruno , Fioravanti Marisa , Viviani Barbara , Marinovich Marina , Govoni Stefano , Galli Corrado L. 
Published: April 2014

Abstract
Elderly subjects are at increased risk of pneumonia, influenza, and tuberculosis. Besides the known age-related decrease in mechanisms for mechanical clearance of the lungs, impaired alveolar macrophage function contributes to the increased risk of illness in the elderly. We have previously shown that age-induced macrophage immunodeficiencies are associated with a defective system for anchoring protein kinase C. Castration of young male rats produces effects on alveolar macrophages similar to those of aging, suggesting a relationship between circulating sex hormones, particularly androgens, and the decreases in the receptor for activated C kinase (RACK-1) and macrophage function observed. The aging process in humans and rats is associated with a decline in the plasma concentrations of dehydroepiandrosterone (DHEA) and its sulfate, among other steroid hormones. We report here that in vitro and in vivo administration of DHEA to rats restores the age-decreased level of RACK-1 and the LPS-stimulated production of TNF-α in alveolar macrophages. DHEA in vivo also restores age-decreased spleen mitogenic responses and the level of RACK-1 expression. These findings suggest that the age-related loss in immunological responses, linked to defective pathways of signal transduction, are partially under hormonal control and can be restored by appropriate replacement therapy.
Distinct Role of p38 and c-Jun N-Terminal Kinases in IL-10-Dependent and IL-10-Independent Regulation of the Costimulatory Molecule B7.2 in Lipopolysaccharide-Stimulated Human Monocytic Cells
Authors: Lim Wilfred , Ma Wei , Gee Katrina , Aucoin Susan , Nandan Devki , Diaz-Mitoma Francisco , Kozlowski Maya , Kumar Ashok 
Published: April 2014

AbstractThe costimulatory molecule B7.2 (CD86) plays a vital role in immune activation and development of Th responses. The molecular mechanisms by which B7.2 expression is regulated are not understood. We investigated the role of mitogen-activated protein kinases (MAPK) in the regulation of B7.2 expression in LPS-stimulated human monocytic cells. LPS stimulation of human monocytes resulted in the down-regulation of B7.2 expression that could be abrogated by anti-IL-10 Abs. Furthermore, SB202190, a specific inhibitor of p38 MAPK, inhibited LPS-induced IL-10 production and reversed B7.2 down-regulation, suggesting that LPS-induced B7.2 down-regulation may be mediated, at least in part, via regulation of IL-10 production by p38 MAPK. In contrast to human promonocytic THP-1 cells that are refractory to the inhibitory effects of IL-10, LPS stimulation enhanced B7.2 expression. This IL-10-independent B7.2 induction was not influenced by specific inhibitors of either p38 or p42/44 MAPK. To ascertain the role of the c-Jun N-terminal kinase (JNK) MAPK, dexamethasone, an inhibitor of JNK activation, was used, which inhibited LPS-induced B7.2 expression. Transfection of THP-1 cells with a plasmid expressing a dominant-negative stress-activated protein/extracellular signal-regulated kinase kinase 1 significantly reduced LPS-induced B7.2 expression, thus confirming the involvement of JNK. To study the signaling events downstream of JNK activation, we show that dexamethasone did not inhibit LPS-induced NF-κB activation in THP-1 cells, suggesting that JNK may not be involved in NF-κB activation leading to B7.2 expression. Taken together, our results reveal the distinct involvement of p38 in IL-10-dependent, and JNK in IL-10-independent regulation of B7.2 expression in LPS-stimulated monocytic cells.
Impaired Resistance and Enhanced Pathology During Infection with a Noninvasive, Attaching-Effacing Enteric Bacterial Pathogen,Citrobacter rodentium, in Mice Lacking IL-12 or IFN-γ
Authors: Simmons Cameron P. , Goncalves Nathalie S. , Ghaem-Maghami Marjan , Bajaj-Elliott Mona , Clare Simon , Neves Bianca , Frankel Gad , Dougan Gordon , MacDonald Thomas T. 
Published: April 2014

AbstractMice infected with Citrobacter rodentium represent an excellent model in which to examine immune defenses against an attaching-effacing enteric bacterial pathogen. Colonic tissue from mice infected with C. rodentium harbors increased transcripts for IL-12 and IFN-γ and displays mucosal pathology compared with uninfected controls. In this study, the role of IL-12 and IFN-γ in host defense and mucosal injury during C. rodentium infection was examined using gene knockout mice. IL-12p40−/− and IFN-γ−/− mice were significantly more susceptible to mucosal and gut-derived systemic C. rodentium infection. In particular, a proportion of IL-12p40−/− mice died during infection. Analysis of the gut mucosa of IL-12p40−/− mice revealed an influx of CD4+ T cells and a local IFN-γ response. Infected IL-12p40−/− and IFN-γ−/− mice also mounted anti-Citrobacter serum and gut-associated IgA responses and strongly expressed inducible NO synthase (iNOS) in mucosal tissue, despite diminished serum nitrite/nitrate levels. However, iNOS does not detectably contribute to host defense against C. rodentium, as iNOS−/− mice were not more susceptible to infection. However, C57BL/6 mice infected with C. rodentium up-regulated expression of the mouse β-defensin (mBD)-1 and mBD-3 in colonic tissue. In contrast, expression of mBD-3, but not mBD-1, was significantly attenuated during infection of IL-12- and IFN-γ-deficient mice, suggesting mBD-3 may contribute to host defense. These studies are among the first to examine mechanisms of host resistance to an attaching-effacing pathogen and show an important role for IL-12 and IFN-γ in limiting bacterial infection of the colonic epithelium.
Role of Galectin-3 as an Adhesion Molecule for Neutrophil Extravasation During Streptococcal Pneumonia
Authors: Sato Sachiko , Ouellet Nathalie , Pelletier Isabelle , Simard Marie , Rancourt Ann , Bergeron Michel G. 
Published: April 2014

AbstractRecruitment of neutrophils from blood vessels to sites of infection represents one of the most important elements of innate immunity. Movement of neutrophils across blood vessel walls to the site of infection first requires that the migrating cells firmly attach to the endothelial wall. Generally, neutrophil extravasation is mediated at least in part by two classes of adhesion molecules, β2 integrins and selectins. However, in the case of streptococcal pneumonia, recent studies have revealed that a significant proportion of neutrophil diapedesis is not mediated by the β2 integrin/selectin paradigm. Galectin-3 is a β-galactoside-binding lectin implicated in inflammatory responses as well as in cell adhesion. Using an in vivo streptococcal pneumonia mouse model, we found that accumulation of galectin-3 in the alveolar space of streptococcus-infected lungs correlates closely with the onset of neutrophil extravasation. Furthermore, immunohistological analysis of infected lung tissue revealed the presence of galectin-3 in the lung tissue areas composed of epithelial and endothelial cell layers as well as of interstitial spaces. In vitro, galectin-3 was able to promote neutrophil adhesion to endothelial cells. Promotion of neutrophil adhesion by galectin-3 appeared to result from direct cross-linking of neutrophils to the endothelium and was dependent on galectin-3 oligomerization. Together, these results suggest that galectin-3 acts as an adhesion molecule that can mediate neutrophil adhesion to endothelial cells. However, accumulation of galectin-3 in lung was not observed during neutrophil emigration into alveoli induced by Escherichia coli infection, where the majority of neutrophil emigration is known to be β2 integrin dependent. Thus, based on our results, we propose that galectin-3 plays a role in β2 integrin-independent neutrophil extravasation, which occurs during alveolar infection with Streptococcus pneumoniae.
Eotaxin-2 Generation Is Differentially Regulated by Lipopolysaccharide and IL-4 in Monocytes and Macrophages
Authors: Watanabe Kimiko , Jose Peter J. , Rankin Sara M. 
Published: April 2014

AbstractThe eotaxins are a family of CC chemokines that coordinate the recruitment of inflammatory cells, in particular eosinophils, to sites of allergic inflammation. The cDNA for eotaxin-2 (CC chemokine ligand 24) was originally isolated from an activated monocyte library. In this study, we show for the first time that peripheral blood monocytes generate bioactive eotaxin-2 protein constitutively. Eotaxin-2 production was significantly up-regulated when monocytes were stimulated with the proinflammatory cytokine IL-1β and the microbial stimuli, LPS and zymosan. In contrast, the Th2 cytokines, IL-4 and IL-13, and the proinflammatory cytokine, TNF-α, acting alone or in combination, did not enhance the generation of eotaxin-2 by monocytes. Indeed, IL-4 suppressed the generation of eotaxin-2 by LPS-stimulated monocytes. Although other chemokines, including macrophage-inflammatory protein-1α, monocyte chemoattractant protein-1, macrophage-derived chemokine, and IL-8 were generated by monocytes, eotaxin-1 (CC chemokine ligand 11) could not be detected in the supernatants of monocytes cultured in the presence or absence of any of the stimuli used in the above experiments. Furthermore, human dermal fibroblasts that produce eotaxin-1 did not generate eotaxin-2 under basal conditions or when stimulated with specific factors, including IL-4, IL-13, TNF-α, and LPS. When monocytes were differentiated into macrophages, their constitutive generation of eotaxin-2 was suppressed. Moreover, IL-4, but not LPS, up-regulated the production of eotaxin-2 by macrophages. Taken as a whole, these results support a role for macrophage-derived eotaxin-2 in adaptive immunity, with a Th2 bias. In contrast, a role for monocyte-derived eotaxin-2 is implicated in innate immunity.
Expression and Function of the C5a Receptor in Rat Alveolar Epithelial Cells
Authors: Riedemann Niels C. , Guo Ren-Feng , Sarma Vidya J. , Laudes Ines J. , Huber-Lang Markus , Warner Roscoe L. , Albrecht Eric A. , Speyer Cecilia L. , Ward Peter A. 
Published: April 2014

AbstractAlthough alveolar epithelial cells (AEC) form an important barrier for host defenses in the lung, there is limited information about ways in which AEC can directly participate in the lung inflammatory response. In the current studies, primary cultures of rat AEC (RAEC) have been shown to specifically bind recombinant rat C5a at high affinity and in a saturable manner. This binding was enhanced in a time-dependent manner by pre-exposure of RAEC to LPS, IL-6, or TNF-α, the increased binding of C5a being associated with increased levels of mRNA for the C5a receptor (C5aR). Exposure of RAEC to C5a also caused increased expression of mRNA for C5aR. As compared with exposure of RAEC to LPS or to C5a alone, exposure to the combination caused enhanced production of TNF-α, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant-1, as well as increased intracellular levels of IL-1β. These data indicate that RAEC, when activated, have enhanced binding of C5a in association with increased mRNA for C5aR. The functional outcome is enhanced release of proinflammatory mediators. These data underscore the phlogistic potential of RAEC and the ability of C5a to enhance the phlogistic responses of RAEC.
Biological Activities of Ecalectin: A Novel Eosinophil-Activating Factor
Authors: Matsumoto Ryoji , Hirashima Mitsuomi , Kita Hirohito , Gleich Gerald J. 
Published: April 2014

AbstractEcalectin, produced by Ag-stimulated T lymphocytes, is a potent eosinophil-specific chemoattractant in vitro as well as in vivo and thus is implicated in allergic responses. Ecalectin differs structurally from other known eosinophil chemoattractants (ECAs); ecalectin belongs to the galectin family defined by their affinity for β-galactosides and by their conserved carbohydrate recognition domains. These characteristic features suggest that ecalectin has unique activities associated with allergic inflammation besides ECA activity. Conversely, ecalectin may mediate ECA activity by binding to a receptor of a known ECA via affinity for the β-galactosides present on this receptor. In this study, we have tested whether ecalectin mediates ECA activity by binding to a receptor of a known ECA, and we have assessed its effects on eosinophils. Ecalectin did not mediate ECA activity by binding to the IL-5R or to CCR3. Also, the ECA activity of ecalectin was mainly chemokinetic. In addition, ecalectin induced concentration-dependent eosinophil aggregation, a marker for eosinophil activation. Ecalectin induced concentration-dependent superoxide production from eosinophils but did not induce degranulation; usually these two events are coupled in eosinophil activation. Moreover, ecalectin directly prolonged eosinophil survival in vitro and did not trigger eosinophils to secrete cytokines that prolong eosinophil survival. These results demonstrate that ecalectin has several unique effects on eosinophils. Therefore, we conclude that ecalectin is a novel eosinophil-activating factor. Presumably, these effects allow ecalectin to play a distinctive role in allergic inflammation.
Lipopolysaccharide Induces Rapid Production of IL-10 by Monocytes in the Presence of Apoptotic Neutrophils
Authors: Byrne Aideen , Reen Denis J. 
Published: April 2014

AbstractThere is growing evidence that apoptotic neutrophils have an active role to play in the regulation and resolution of inflammation following phagocytosis by macrophages and dendritic cells. However, their influence on activated blood monocytes, freshly recruited to sites of inflammation, has not been defined. In this work, we examined the effect of apoptotic neutrophils on cytokine production by LPS-activated monocytes. Monocytes stimulated with LPS in the presence of apoptotic neutrophils for 18 h elicited an immunosuppressive cytokine response, with enhanced IL-10 and TGF-β production and only minimal TNF-α and IL-1β cytokine production. Time-kinetic studies demonstrated that IL-10 production was markedly accelerated in the presence of apoptotic neutrophils, whereas there was a sustained reduction in the production of TNF-α and IL-1β. This suppression of proinflammatory production was not reversible by depletion of IL-10 or TGF-β or by addition of exogenous IFN-γ. It was demonstrated, using Transwell experiments, that monocyte-apoptotic cell contact was required for induction of the immunosuppressive monocyte response. The response of monocytes contrasted with that of human monocyte-derived macrophages in which there was a reduction in IL-10 production. We conclude from these data that interaction between activated monocytes and apoptotic neutrophils creates a unique response, which changes an activated monocyte from being a promoter of the inflammatory cascade into a cell primed to deactivate itself and other cells.
Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice
Authors: Yagi Ryouji , Nagai Haruko , Iigo Yutaka , Akimoto Toshihiro , Arai Takao , Kubo Masato 
Published: April 2014

AbstractAtopic dermatitis (AD) is a pruritic inflammatory skin disease characterized by elevation of plasma levels of total IgE, infiltration of mast cells and eosinophils, and the expression of cytokines by Th2 T cells. However, the role of Th2 cells in the pathogenesis of AD is not fully understood. In this study we examined the NC/Nga (NC) mouse model of AD and established STAT6-deficient (SATA6−/−) NC mice to investigate the relevance of IL-4-mediated immune responses. Surprisingly, these mice elicited AD-like skin lesions at equivalent frequency and time of onset compared with normal NC littermates. Histological features of the lesion in STAT6−/− NC mice fulfilled the criteria for the pathogenesis of AD, although these mice fail to produce IgE and Th2 cytokines. The lymph nodes proximal to the regions of skin that developed lesions exhibited massive enlargement elicited by the accumulation of activated IFN-γ-secreting T cells. Moreover, caspase I, IL-18, IL-12, and IFN-γ are found to be highly expressed at the skin lesion, occurring simultaneously with elevation of eotaxin 2 and CCR3 expression. Therefore, the Th2-mediated immune response is not necessary for the development of AD-like skin disease in NC mice. The skin microenvironment that favored IFN-γ production tightly correlates with the skin disease in NC mice through the infiltration of eosinophils.
Cutting Edge: Inhibitory Functions of the Killer Cell Lectin-Like Receptor G1 Molecule During the Activation of Mouse NK Cells
Authors: Robbins Scott H. , Nguyen Khuong B. , Takahashi Nobuaki , Mikayama Toshifumi , Biron Christine A. , Brossay Laurent 
Published: April 2014

AbstractThe killer cell lectin-like receptor G1 (KLRG1) is the mouse homolog of the rat mast cell function-associated Ag and contains an immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic domain. In this study we demonstrate that both pathogenic and nonpathogenic in vivo activation of NK cells induces the expression of KLRG1 on their cell surface. Upon infection with murine CMV, this induction peaks between days 5 and 7 with ∼90% of the NK cells expressing KLRG1. On day 1.5 post-murine CMV infection of C57BL/6 mice, the main producers of IFN-γ are the KLRG1-negative NK cells. This effect has been recapitulated in vitro as we show that engagement of KLRG1 on a transfected NK cell line inhibits both cytokine production and NK cell-mediated cytotoxicity. Taken together, these data illustrate the crucial role played by KLRG1 during the termination of mouse NK cell activation.
Cutting Edge: Recruitment of the Ancestral fyn Gene During Emergence of the Adaptive Immune System
Authors: Picard Christophe , Gilles André , Pontarotti Pierre , Olive Daniel , Collette Yves 
Published: April 2014

Abstract
The adaptive immune system (AIS) is characterized by the MHC molecules and the rearranging Ag receptors, and was established in a common ancestor of jawed vertebrates. Fyn, a Src-family tyrosine kinases, is important for normal development and function of T lymphocytes and neuronal cells. Indeed, as the result of an alternative splicing of a distinct exon 7, fyn encodes for two isoforms, FynT in T lymphocytes and FynB in the brain. How this alternative splicing of fyn transcripts has emerged and evolved in relation to the setting of the AIS remains to be established. In this study, we show that exon capture in a vertebrate ancestor by the fynT-like gene has yielded a novel fyn-encoded isoform, fynB. Unexpectedly, the newly established AIS recruited the ancestral Fyn isoform, FynT, whereas the CNS expresses the most recent one, FynB. These results shed new light on the emergence of the AIS.
Cutting Edge: CD83 Regulates the Development of Cellular Immunity
Authors: Scholler Nathalie , Hayden-Ledbetter Martha , Dahlin Amber , Hellström Ingegerd , Hellström Karl Erik , Ledbetter Jeffrey A. 
Published: April 2014

Abstract
We recently found that human CD83, a marker of mature dendritic cells, is an adhesion receptor that binds to resting monocytes and a subset of activated CD8+ T cells. We injected CD83-Ig into mice transplanted with the immunogenic P815 mastocytoma and showed that it significantly enhanced the rate of tumor growth and inhibited the development of cytotoxic T cells. In contrast, mice immunized with CD83-transfected K1735 cells, a poorly immunogenic melanoma, could prevent the outgrowth of wild-type K1735 cells. Studies performed in vitro with human PBL showed that coimmobilized CD83-Ig and anti-CD3 enhanced T cell proliferation and increased the proportion of CD8+ T cells. CD83-transfected B-lymphoblastoid T51 cells stimulated T cell proliferation more effectively than untransfected T51 cells in MLR cultures and increased the generation of cytolytic T cells. We conclude that CD83 is a functionally important receptor that can regulate the development of cellular immunity by interacting with its ligand(s).
Cutting Edge: VacA, a Vacuolating Cytotoxin of Helicobacter pylori, Directly Activates Mast Cells for Migration and Production of Proinflammatory Cytokines
Authors: Supajatura Volaluck , Ushio Hiroko , Wada Akihiro , Yahiro Kinnosuke , Okumura Ko , Ogawa Hideoki , Hirayama Toshiya , Ra Chisei 
Published: April 2014

Abstract
Mucosal mast cells strategically located at the optimal site interact with invading bacteria. Presence of VacA, the virulent Helicobacter pylori cytotoxin, is correlated with the severity of H. pylori-induced gastritis. To examine the mechanisms of inflammation in H. pylori-induced gastritis, we administered VacA to the mice. Inoculation of VacA resulted in epithelium vacuolization and marked infiltrations of mast cells and mononuclear cells into the mucosal epithelium within 24 h. In an in vitro study using bone marrow-derived mast cells, VacA directly bound and showed a chemotactic activity to the mast cell. In addition, VacA induced bone marrow-derived mast cells to produce proinflammatory cytokines, TNF-α, macrophage-inflammatory protein-1α, IL-1β, IL-6, IL-10, and IL-13 in a dose-dependent manner without causing degranulation. The present study suggests that early activation of mast cells by VacA may be the host early response to clear the bacteria and also may contribute to the pathogenesis of H. pylori-induced gastritis.