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Inflammatory Cell Activation (inflammatory + cell_activation)
Selected AbstractsAcute Alcohol Inhibits the Induction of Nuclear Regulatory Factor ,B Activation Through CD14/Toll-Like Receptor 4, Interleukin-1, and Tumor Necrosis Factor Receptors: A Common Mechanism Independent of Inhibitory ,B, Degradation?ALCOHOLISM, Issue 11 2002Pranoti Mandrekar Background Nuclear translocation and DNA binding of the nuclear factor ,B (NF-,B) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-,B activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-,B activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-,B when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors. Methods Human peripheral blood monocytes were treated with LPS, TNF,, and IL-1, in the presence or absence of 25mM alcohol for 1 hr. NF-,B activation was determined by electrophoretic mobility shift assays using nuclear extracts. Inhibitory ,B, (I,B,) was estimated by Western blotting in cytoplasmic extracts. Chinese hamster ovary cells expressing human CD14 were treated with LPS in the presence or absence of alcohol to study NF-,B and I,B, regulation. Results Our results indicate that acute alcohol inhibits IL-1,- and TNF,-induced NF-,B activation. We further show in CD14/toll-like receptor 4,expressing Chinese hamster ovary cells the specificity of alcohol-mediated inhibition of NF-,B via the toll-like receptor 4/CD14 receptors. Inhibition of NF-,B by acute alcohol was concomitant with decreased levels of the I,B, molecule in the cytoplasm of LPS, IL-1, and TNF,-activated monocytes. Conclusions These data suggest a unique, I,B,-independent pathway for the inhibition of NF-,B activation by acute alcohol in monocytes. Universal inhibition of NF-,B by acute alcohol via these various receptor systems suggests a target for the effects of alcohol in the NF-,B activation cascade that is downstream from I,B, degradation. Further, these results demonstrate that acute alcohol is a potent inhibitor of NF-,B activation by mediators of early (LPS) or late (IL-1, TNF,) stages of inflammation in monocytes. [source] CD40 and OX40 ligand are differentially regulated on asthmatic airway smooth muscleALLERGY, Issue 7 2009D. I. Krimmer Background:, CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-,) and interferon-gamma (IFN-,) on ASM CD40 and OX40L expression. Methods:, CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-, and/or IFN-, was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. Results:, Interferon-, and TNF-, synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-, reduced TNF-,-induced OX40L expression to a similar extent in both cell types. TNF-, and IFN-, induced CD40 via nuclear factor-,B (NF-,B) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-,B and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-,B, but these were not statistically significant. The reduced OX40L expression with TNF-, and IFN-, involved extracellular regulated kinase 1/2 activation. Conclusion:, Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-, may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression. [source] Platelet Recruitment in the Murine Hepatic Microvasculature During Experimental Sepsis: Role of NeutrophilsMICROCIRCULATION, Issue 2 2006GEORG SINGER ABSTRACT Objectives: Sepsis is a major clinical problem that often results in the dysfunction or failure of multiple organs, including the liver. While inflammatory cell activation has been implicated as an early critical event in sepsis-induced liver dysfunction, there is growing evidence for the involvement of activated platelets in this pathologic process. Methods: Intravital microscopy was used in this study to assess the magnitude and time course of platelet adhesion in the liver microcirculation during experimental sepsis and to determine whether the platelet accumulation is linked to leukocyte infiltration. The adhesion of platelets and leukocytes in terminal hepatic venules (THV) and sinusoids was quantified at 2, 4, and 6 h after abdominal sepsis induced by cecal ligation and puncture (CLP). Results: While the rolling and firm adhesion of platelets and leukocytes in THV were not altered in the first 2 h after CLP, platelet recruitment was observed at 4 h and further elevated at 6 h after CLP. Leukocyte adhesion in THV exhibited a similar time course. A similar accumulation of blood cells in sinusoids was noted after CLP. This was accompanied by an increased number of nonperfused sinusoids. CLP-induced leukocyte and platelet recruitment in THV and sinusoids was attenuated in mice rendered neutropenic with anti-neutrophil serum. Conclusion: These findings indicate that sepsis is associated with a neutrophil-dependent recruitment of platelets in the liver microcirculation that impairs sinusoidal perfusion and may contribute to the liver dysfunction associated with sepsis. [source] Histamine H1 -receptor-mediated release of preformed mediators and cytokines and airway remodellingCLINICAL & EXPERIMENTAL ALLERGY REVIEWS, Issue 3 2002M. Triggiani Summary Histamine is a chemical mediator synthesized and stored within secretory granules of human basophils and mast cells [1,2]. The central role of histamine as a mediator of allergic reactions is unchallenged and is also supported by the efficacy of antihistamines in relieving symptoms of the early-phase allergic response [3]. However, a recent hypothesis suggests that the role of histamine is not limited to the early-phase reaction, but may also have a role in the regulation of the late-phase response. This paper describes certain effects of histamine on human inflammatory cell activation, and in particular, its ability to directly activate human lung macrophages and the molecular mechanism for this interaction. These studies have important implications for the therapeutic potential of antihistamines in the treatment of patients with allergic disorders. [source] Leukotriene pathway genetics and pharmacogenetics in allergyALLERGY, Issue 6 2009N. P. Duroudier Leukotrienes (LT) are biologically active lipid mediators known to be involved in allergic inflammation. Leukotrienes have been shown to mediate diverse features of allergic conditions including inflammatory cell chemotaxis/activation and smooth muscle contraction. Cysteinyl leukotrienes (LTC4, LTD4 and, LTE4) and the dihydroxy leukotriene LTB4 are generated by a series of enzymes/proteins constituting the LT synthetic pathway or 5-lipoxygenase (5-LO) pathway. Their function is mediated by interacting with multiple receptors. Leukotriene receptor antagonists (LTRA) and LT synthesis inhibitors (LTSI) have shown clinical efficacy in asthma and more recently in allergic rhinitis. Despite growing knowledge of leukotriene biology, the molecular regulation of these inflammatory mediators remains to be fully understood. Genes encoding enzymes of the 5-LO pathway (i.e. ALOX5, LTC4S and LTA4H) and encoding for LT receptors (CYSLTR1/2 and LTB4R1/2) provide excellent candidates for disease susceptibility and severity; however, their role remains unclear. Preliminary data also suggest that 5-LO pathway/receptor gene polymorphism can predict patient responses to LTSI and LTRA; however, the exact mechanisms require elucidation. The aim of this review was to summarize the recent advances in the knowledge of these important mediators, focusing on genetic and pharmacogenetic aspects in the context of allergic phenotypes. [source] | ||||||||||