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Extracellular signal‐regulated kinase plays an essential role in endothelin‐1‐induced homotypic adhesion of human neutrophil granulocytes
Author(s) -
József Levente,
Khreiss Tarek,
Fournier Alain,
Chan John S D,
Filep János G
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704561
Subject(s) - mapk/erk pathway , microbiology and biotechnology , kinase , cd18 , neutrophil extracellular traps , signal transduction , chemistry , biology , integrin alpha m , inflammation , immunology , flow cytometry
Endothelin‐1 (ET‐1) stimulates integrin‐dependent adhesion of neutrophil granulocytes to endothelial cells, one of the early key events in acute inflammation. However, the signalling pathway(s) of ET‐1‐stimulated neutrophil adhesive responses has not been elucidated. Previous studies indicated that extracellular signal‐regulated kinase (ERK) activation could mediate rapid responses of neutrophil granulocytes to various stimuli. In this study, we investigated the role of ERK signalling in human neutrophil granulocytes challenged with ET‐1. ET‐1 rapidly down‐regulated the expression of L‐selectin and up‐regulated the expression of CD11b/CD18 on the neutrophil surface. Concomitantly, ET‐1 induced homotypic adhesion (aggregation) of neutrophils, that was blocked by a monoclonal antibody to CD18. ET‐1, through ET A receptors, evoked activation of Ras and subsequent phosphorylation of Raf‐1, mitogen‐activated protein kinase kinase (MAPK/ERK kinase) and ERK 1/2. ERK activation by ET‐1 was rapid, concordant with the kinetics of ET‐1‐stimulated neutrophil aggregation. Neutrophil responses to ET‐1 were markedly attenuated by the MAPK/ERK kinase inhibitor PD98059, whereas inhibitors of p38 MAPK, tyrosine kinases and phosphatidylinositol 3‐kinase had no detectable effects. We have observed a tight correlation between neutrophil ERK activation and homotypic adhesion. These data indicate an essential role for ERK in mediating ET‐1‐stimulated adhesive responses of human neutrophil granulocytes.British Journal of Pharmacology (2002) 135 , 1167–1174; doi: 10.1038/sj.bjp.0704561