A crucial role for TNF-α in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5: RESEARCH PAPER
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Background and purpose: Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP-2/CXCL2 and LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice. Experimental approach: Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)-α. Cytokine and chemokine levels were determined in peritoneal exudates and in supernatants of macrophages and mast cells by elisa. CXCR2 and intercellular adhesion molecule 1 (ICAM-1) expression was determined using immunohistochemistry and confocal microscopy. Key results: Antigen challenge induced dose- and time-dependent neutrophil recruitment and production of KC/CXCL1, LIX/CXCL5 and TNF-α, but not MIP-2/CXCL2, in peritoneal exudates. Neutrophil recruitment was inhibited by treatment with reparixin (CXCR1/2 antagonist), anti-KC/CXCL1, anti-LIX/CXCL5 or anti-TNF-α antibodies and in tumour necrosis factor receptor 1-deficient mice. Intraperitoneal injection of KC/CXCL1 and LIX/CXCL5 induced dose- and time-dependent neutrophil recruitment and TNF-α production, which were inhibited by reparixin or anti-TNF-α treatment. Macrophages and mast cells expressed CXCR2 receptors. Increased macrophage numbers enhanced, while cromolyn sodium (mast cell stabilizer) diminished, LIX/CXCL5-induced neutrophil recruitment. Macrophages and mast cells from immunized mice produced TNF-α upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM-1 on mesenteric vascular endothelium, which was inhibited by anti-TNF-α or anti-LIX/CXCL5. Conclusion and implications: Following antigen challenge, CXCR2 ligands are produced and act on macrophages and mast cells triggering the production of TNF-α, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM-1. © 2009 The British Pharmacological Society.
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3 [3 Tert Butylthio 1 (4 Chlorobenzyl) 5 Isopropyl 2 Indolyl] 2,2 Dimethylpropionic Acid, Antigen, Serum Albumin, Bovine, Chemokine Receptor Antagonist, Chemokine Receptor Ccr2, Chemokine Receptor Cxcr1, Chemokine Receptor Cxcr2, Cromoglycate Disodium, Cxcl1 Chemokine, Cxcl1 Chemokine Antibody, Cxcl2 Chemokine, Cytokine, Cytokine Antibody, Epithelial Derived Neutrophil Activating Factor 78, Epithelial Derived Neutrophil Activating Factor 78 Antibody, Intercellular Adhesion Molecule-1, Ligand, Reparixin, Stabilizing Agent, Tumor Necrosis Factor-alpha, Tumor Necrosis Factor Alpha Antibody, Tumor Necrosis Factor Receptor 1, Unclassified Drug, Animals Cell, Animals Experiment, Animals Model, Animals Tissue, Confocal Microscopy, Controlled Study, Dose Time Effect Relation, Enzyme-linked Immunosorbent Assay, Immunization, Immunohistochemistry, Inflammation, Macrophage, Mast Cell, Mesenteric Vein, Methylation, Mouse, Neutrophil Chemotaxis, Nonhuman, Peritoneum Exudate, Priority Journal, Protein Expression, Supernatant, Vascular Endothelium, Animal, Antibodies, Cattle, Cxcl1 Chemokine, Chemokine Cxcl5, Intercellular Adhesion Molecule-1, Macrophages, Peritoneal, Mast Cells, Mice, Mice, Inbred Balb C, Mice, Inbred C57bl, Mice, Knockout, Neutrophils, Peritonitis, Receptors, Interleukin-8a, Receptors, Interleukin-8b, Receptors, Tumor Necrosis Factor, Type I, Serum Albumin, Sulfonamides, Tumor Necrosis Factor-alpha