The Journal of Experimental Medicine
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Published 17 February 2004. doi:10.1084/jem.20031771
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 4, 449-458
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p38-MAPK Signals Survival by Phosphorylation of Caspase-8 and Caspase-3 in Human Neutrophils

Maria Alvarado-Kristensson1, Fredrik Melander1, Karin Leandersson1, Lars Rönnstrand2, Christer Wernstedt3, and Tommy Andersson1

1 Division of Experimental Pathology, Department of Laboratory Medicine, Lund University, U-MAS, SE-205 02 Malmö, Sweden
2 Division of Experimental Clinical Chemistry, Department of Laboratory Medicine, Lund University, U-MAS, SE-205 02 Malmö, Sweden
3 Ludwig Institute for Cancer Research, Biomedical Center, SE-751 24 Uppsala, Sweden

Address correspondence to Maria Alvarado-Kristensson, Experimental Pathology, Lund University, U-MAS, Entrance 78, Floor 3, SE-205 02 Malmö, Sweden. Phone: 46-40-33-76-46; Fax: 46-40-33-73-53; email: maria.alvarado-kristensson{at}exppat.mas.lu.se

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.

Key Words: apoptosis • Fas • inflammation • phosphopeptide mapping • TAT-tagged caspases

Abbreviations used in this paper: AMC, aminomethylcoumarin; IPTG, isopropyl-1-thio-ß-D-galactopyranoside; MAPK, mitogen-activated protein kinase.


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