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Endothelin-1 induces neutrophil recruitment in adaptive inflammation via TNFα and CXCL1/CXCR2 in mice

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Endothelin mediates neutrophil recruitment during innate inflammation. Herein we address whether endothelin-1 (ET-1) is involved in neutrophil recruitment in adaptive inflammation in mice, and its mechanisms. Pharmacological treatments were used to determine the role of endothelin in neutrophil recruitment to the peritoneal cavity of mice challenged with antigen (ovalbumin) or ET-1. Levels of ET-1, tumour necrosis factor α (TNFα), and CXC chemokine ligand 1 (CXCL1) were determined by enzyme-linked immunosorbent assay. Neutrophil migration and flow cytometry analyses were performed 4 h after the intraperitoneal stimulus. ET-1 induced dose-dependent neutrophil recruitment to the peritoneal cavity. Treatment with the non-selective ETA/ETB receptor antagonist bosentan, and selective ETA or ETB receptor antagonists BQ-123 or BQ-788, respectively, inhibited ET-1- and ovalbumin-induced neutrophil migration to the peritoneal cavity. In agreement with the above, the antigen challenge significantly increased levels of ET-1 in peritoneal exudates. The ET-1- and ovalbumin-induced neutrophil recruitment were reduced in TNFR1 deficient mice, and by treatments targeting CXCL1 or CXC chemokine receptor 2 (CXCR2); further, treatment with bosentan, BQ-123, or BQ-788 inhibited ET-1- and antigen-induced production of TNFα and CXCL1. Furthermore, ET-1 and ovalbumin challenge induced an increase in the number of cells expressing the Gr1+ markers in the granulocyte gate, CD11c+ markers in the monocyte gate, and CD4+ and CD45+ (B220) markers in the lymphocyte gate in an ETA- and ETB-dependent manner, as determined by flow cytometry analysis, suggesting that ET-1 might be involved in the recruitment of neutrophils and other cells in adaptive inflammation. Therefore, the present study demonstrates that ET-1 is an important mediator for neutrophil recruitment in adaptive inflammation via TNFα and CXCL1/CXCR2-dependent mechanism.

Keywords: TNF-α; TNFα; chemokine; chimiokine; endothelin; endothéline; migration des neutrophiles; neutrophil migration; repertaxin; répertaxine

Document Type: Research Article


Affiliations: 1: Departamento de Patologia, Centro de Ciencias Biologicas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid PR445 KM380, 86051-990, Londrina, Parana, Brazil. 2: Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes, 3900, 14050-990, Ribeirao Preto, Sao Paulo, Brazil. 3: Department of Immunology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Avenida Bandeirantes, 3900, 14050-990, Ribeirao Preto, São Paulo, Brazil.

Publication date: February 20, 2012

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