Extracellular signal-regulated kinase plays an essential role in endothelin-1-induced homotypic adhesion of human neutrophil granulocytes.
1. 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. 2. 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. 3. 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. 4. 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. 5. These data indicate an essential role for ERK in mediating ET-1-stimulated adhesive responses of human neutrophil granulocytes.
József
Levente
L
Research Center, Maisonneuve-Rosemont Hospital and Department of Medicine, University of Montréal, Montréal, Québec, Canada H1T 2M4.
Khreiss
Tarek
T
Fournier
Alain
A
Chan
John S D
JS
Filep
János G
JG
D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects*; D010766:Phosphorylation; D044022:Receptor, Endothelin A; D015854:Up-Regulation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D016177:Macrophage-1 Antigen; D044022:Receptor, Endothelin A; D019041:L-Selectin; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one