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A crucial role for TNF-alpha in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5

Lookup NU author(s): Dr Henrique De Paula Lemos

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Abstract

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)-alpha. 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-alpha, 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-alpha 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-alpha production, which were inhibited by reparixin or anti-TNF-alpha 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-alpha upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM-1 on mesenteric vascular endothelium, which was inhibited by anti-TNF-alpha 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-alpha, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM-1.


Publication metadata

Author(s): Vieira SM, Lemos HP, Grespan R, Napimoga MH, Dal-Secco D, Freitas A, Cunha TM, Verri WAJr, Souza-Junior DA, Jamur MC, Fernandes KS, Oliver C, Silva JS, Teixeira MM, Cunha FQ

Publication type: Article

Publication status: Published

Journal: British Journal of Pharmacology

Year: 2009

Volume: 158

Issue: 3

Pages: 779-789

Print publication date: 01/10/2009

Online publication date: 20/08/2009

ISSN (print): 0007-1188

ISSN (electronic): 1476-5381

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/j.1476-5381.2009.00367.x

DOI: 10.1111/j.1476-5381.2009.00367.x

PubMed id: 19702783


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