Abstract
The signal transduction pathways initiated by opsonized zymosan (OZ) leading to activation of cytosolic phospholipase A(2) (cPLA(2)) in human neutrophils remain obscure. In a previous study, we showed that the activation of cPLA(2) by OZ is tyrosine kinase-dependent. The present study demonstrates that the signals initiated by OZ involve activation of tyrosine kinase Pyk2 but not the formation of the adhesion protein complex, Shc-Grb2-Sos. Stimulation of cPLA(2) activity by OZ is mediated by Fc gamma receptors (FcgammaRs) and not by complement receptors for the C3b protein. Cross-linking of FcgammaRIIA or FcgammaRIIIB induces p38 mitogen-activated protein (MAP) kinase and extracellular regulated kinase (ERK) phosphorylation. The kinetics of cPLA(2) activity stimulated by either of the FcgammaRs or by both is similar to that of p38 MAP kinase and was detected as early as 15 s after stimulation, maintained a plateau for 10 min, and decreased thereafter. ERK activation was detected also within 15 s but decreased significantly 5 min after stimulation. The MEK inhibitor, PD-098059, or the p38 MAP kinase inhibitor, SB-203580, caused a partial inhibition during the time course of cPLA(2) activity, whereas their combination caused a total inhibition. Thus, although ERK activation is significantly shorter than that of p38 MAP kinase, it is equally required for activation and maintenance of cPLA(2) activity by occupancy of a single receptor, FcgammaRIIA or FcgammaRIIIB.
Highlights
The signal transduction pathways initiated by opsonized zymosan (OZ) leading to activation of cytosolic phospholipase A2 in human neutrophils remain obscure
We have previously shown the involvement of the mitogen-activated protein (MAP) kinase, ERK1/2, in activating cytosolic phospholipase A2 (cPLA2) and superoxide production in human neutrophils stimulated with opsonized zymosan (OZ) as a model for
The Role of p38 MAP Kinase and extracellular regulated kinase (ERK) in cPLA2 Activation by OZ—In a previous paper [28], we demonstrated that OZ stimulates ERK1 and ERK2 activity in human neutrophils and that ERK is involved in activation of cPLA2
Summary
(Received for publication, August 25, 1999, and in revised form, February 1, 2000). From the ‡Laboratory of Infectious Diseases, Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev and Soroka Medical Center, Beer Sheva 84105, Israel and the §Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100 Israel. The present study demonstrates that the signals initiated by OZ involve activation of tyrosine kinase Pyk but not the formation of the adhesion protein complex, ShcGrb2-Sos. Stimulation of cPLA2 activity by OZ is mediated by Fc ␥ receptors (Fc␥Rs) and not by complement receptors for the C3b protein. Cross-linking of Fc␥RIIA or Fc␥RIIIB induces p38 mitogen-activated protein (MAP) kinase and extracellular regulated kinase (ERK) phosphorylation. ERK activation was detected within 15 s but decreased significantly 5 min after stimulation. ERK activation is significantly shorter than that of p38 MAP kinase, it is required for activation and maintenance of cPLA2 activity by occupancy of a single receptor, Fc␥RIIA or Fc␥RIIIB. The binding of immune complexes by polymorphonuclear neutrophil receptors induces essential host defense and inflammatory responses such as adhesion, phagocytosis of antibody-coated mi-
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