p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils
2004 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 199, no 4, 449-458 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2004. Vol. 199, no 4, 449-458 p.
Apoptosis, Caspases/antagonists & inhibitors/*blood, Cell Survival/physiology, Humans, Inflammation/blood, Mitogen-Activated Protein Kinases/*blood, Neutrophils/cytology/*enzymology, Phosphorylation, Research Support; Non-U.S. Gov't, Signal Transduction/physiology, p38 Mitogen-Activated Protein Kinases
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-72995DOI: 10.1084/jem.20031771PubMedID: 14970175OAI: oai:DiVA.org:uu-72995DiVA: diva2:100906