p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils.

Neutrophil apoptosis occurs both in the bloodstream and in the tissue and is considered essential for the resolution of an inflammatory process. Here, we show that p38-mitogen-activated protein kinase (MAPK) associates to caspase-8 and caspase-3 during neutrophil apoptosis and that p38-MAPK activity, previously shown to be a survival signal in ...
these primary cells, correlates with the levels of caspase-8 and caspase-3 phosphorylation. In in vitro experiments, immunoprecipitated active p38-MAPK phosphorylated and inhibited the activity of the active p20 subunits of caspase-8 and caspase-3. Phosphopeptide mapping revealed that these phosphorylations occurred on serine-364 and serine-150, respectively. Introduction of mutated (S150A), but not wild-type, TAT-tagged caspase-3 into primary neutrophils made the Fas-induced apoptotic response insensitive to p38-MAPK inhibition. Consequently, p38-MAPK can directly phosphorylate and inhibit the activities of caspase-8 and caspase-3 and thereby hinder neutrophil apoptosis, and, in so doing, regulate the inflammatory response.
Mesh Terms:
Apoptosis, Caspase 3, Caspase 8, Caspase Inhibitors, Caspases, Cell Survival, Humans, Inflammation, Mitogen-Activated Protein Kinases, Neutrophils, Phosphorylation, Signal Transduction, p38 Mitogen-Activated Protein Kinases
J. Exp. Med.
Date: Feb. 16, 2004
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