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(Received for publication, August 8, 1996, and in revised form, October 16, 1996)
,
and
From the Activation of polymorphonuclear leukocytes (PMN)
by chemotactic peptides initiates a series of functional responses that
serve to eliminate pathogens. The intermediate steps that link
engagement of the chemoattractant receptor to the microbicidal
responses involve protein kinases that have yet to be identified. In
this study we detected in human PMN the presence of p38
mitogen-activated protein kinase (MAPK), which became rapidly tyrosine
phosphorylated and activated in response to the chemotactic peptide
N-formyl-methionyl-leucyl-phenylalanine (fMLP).
Pretreatment of PMN with wortmannin, a phosphatidylinositol 3-kinase
inhibitor, or bis-indolylmaleimide, a protein kinase C
antagonist, resulted in partial inhibition of p38 phosphorylation upon
fMLP stimulation. Similarly, phosphorylation of p38 was only partially
inhibited when the fMLP-induced cytosolic calcium transient was
prevented. Stimulation of PMN by the chemoattractant also resulted in
the rapid phosphorylation and activation of MAPK-activated protein
kinase-2 (MAPKAPK-2), which was completely inhibited by the specific
p38 inhibitor, SB203580. The physical interaction of p38 with MAPKAPK-2
was studied by coimmunoprecipitation. These two kinases were found to
be associated in unstimulated PMN but dissociated upon activation of
the cells by fMLP. Together these findings demonstrate the activation
of p38 by chemotactic peptides in human PMN by a process involving
phosphatidylinositol 3-kinase, protein kinase C, and calcium. p38, in
turn, is an upstream activator of MAPKAPK-2.
Division of Cell Biology, Research
Institute, The Hospital for Sick Children and the 
Department of
Biochemistry, University of Toronto, Toronto, Ontario M5G 1X8, Canada
and the ¶ Department of Medicine, University of British
Columbia, and Kinetek Pharmaceuticals Inc., Vancouver,
British Columbia V5Z 1A1, Canada
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