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or FMLP Stimulation1




Departments of
*
Physiology,
Pathology, and
Medicine, University of Connecticut Health Center, Farmington, CT 06030; and
§
Institute for Neuroscience, Northwestern University, Chicago, IL 60611
Mitogen-activated protein (MAP) kinase-mediated signal-transduction
pathways convert extracellular stimulation into a variety of cellular
functions. However, the roles of MAP kinases in neutrophils are not
well understood yet. Protein phosphorylation analysis of cellular MAP
kinases indicates that exposure of human neutrophils to chemotactic
factor FMLP as well as granulocyte-macrophage CSF, PMA, or ionomycin
rapidly induced the activation of p38 and p44/42 MAP kinases, but
stimulation with inflammatory cytokine TNF-
triggered the activation
of p38 MAP kinase only. To study the cellular functions of these MAP
kinases, the inhibitor SB20358, which specifically inhibited enzymatic
activity of cellular p38 MAP kinase, and the inhibitor PD98059, which
specifically blocked the induced protein phosphorylation and activation
of p44/42 MAP kinase in intact neutrophils, were utilized. Inhibition
of the cellular p38 MAP kinase activation almost completely abolished
the TNF-
-stimulated IL-8 production and superoxide generation of
human neutrophils. In addition, the FMLP-induced neutrophil chemotaxis
as well as superoxide generation were suppressed markedly by inhibiting
the activation of cellular p38 MAP kinase, but not p44/42 MAP kinase.
Moreover, RIA indicates that the activation of cellular p38 MAP kinase
was required for the neutrophil IL-8 production stimulated by
granulocyte-macrophage CSF or LPS as well as TNF-
, but not for that
induced by PMA or ionomycin. These results demonstrate that the
activation of cellular p38 MAP kinase is indispensable for the TNF-
-
or FMLP-mediated cellular functions in human neutrophils, and suggest
that p38 MAP kinase may play a different role in response to distinct
stimulation.
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