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RECEPTORS AND SIGNAL TRANSDUCTION

Primary granule release from human neutrophils is potentiated by soluble fibrinogen through a mechanism depending on multiple intracellular signaling pathways

Department of Physiology, Temple University Medical School, Philadelphia, Pennsylvania 19140

Submitted 5 April 2004 ; accepted in final form 27 June 2004

N-Formyl-methionyl-leucyl-phenylalanine (fMLP) is a potent activator of neutrophil degranulation. The intracellular signaling mechanisms involved in the potentiating effect of fibrinogen on fMLP-induced primary granule release from human neutrophils were investigated. Fibrinogen caused a significant leftward shift of the concentration-response curve of fMLP-induced elastase release. An antibody against Mac-1 (CD11b/CD18) prevented the potentiating effect of fibrinogen, suggesting that soluble fibrinogen potentiates fMLP-induced degranulating effect by a mechanism mediated by the integrin Mac-1. Fibrinogen enhanced fMLP-induced tyrosine phosphorylation in human neutrophils and markedly enhanced the phosphorylation of mitogen-activated protein kinases (MAPK) caused by fMLP. However, U0126, an inhibitor of p44/42 MAPK activation, or SB-203580, an inhibitor of p38 MAPK, did not alter the effect of fibrinogen on fMLP-induced elastase release. Wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, and genistein, a nonspecific tyrosine kinase inhibitor, strongly inhibited fMLP-induced elastase release both in the presence and in the absence of fibrinogen. An Akt/PKB inhibitor failed to alter the potentiating effect of fibrinogen, suggesting that the effect of fibrinogen is mediated by Akt-independent pathways. Gö6976, an inhibitor of classical PKC isoforms, caused a significant inhibition of fMLP-induced elastase release in the presence or absence of fibrinogen, while nonselective inhibitors of PKC, Ro 31-8220, GF-109203X, and staurosporine, caused potentiation of fMLP-induced elastase release. We conclude that fibrinogen potentiation of primary granule release induced by fMLP is mediated by the integrin CD11b/CD18 through pathways dependent on PI3K and tyrosine kinases, but other regulatory mechanisms may be also involved.

N-formyl-methionyl-leucyl-phenylalanine; elastase; CD11b

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