p38 MAPK Regulates Group IIa Phospholipase A2 Expression in Interleukin-1β-stimulated Rat Neonatal Cardiomyocytes

Norbert Degousee, Eva Stefanski, Thomas F. Lindsay, David A. Ford, Rohan Shahani, Catherine A. Andrews, Donna J. Thuerauf, Christopher C. Glembotski, Timo J. Nevalainen, Jay Tischfield, Barry B. Rubin

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Group IIa phospholipase A2 (GIIa PLA2) is released by some cells in response to interleukin-1β. The purpose of this study was to determine whether interleukin-1β would stimulate the synthesis and release of GIIa PLA2 from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA2 in the regulation of this process. Whereas GIIa PLA2 mRNA was not identified in untreated cells, exposure to interleukin-1β resulted in the sustained expression of GIIa PLA2 mRNA. Interleukin-1β also stimulated a progressive increase in cellular and extracellular GIIa PLA2 protein levels and increased extracellular PLA2 activity 70-fold. In addition, interleukin-1β stimulated the p38 MAPK-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 MAPK inhibitor, SB202190, decreased interleukin-1β stimulated MAPKAP-K2 activity, GIIa PLA2 mRNA expression, GIIa PLA2 protein synthesis, and the release of extracellular PLA2 activity. Infection with an adenovirus encoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA 2 protein synthesis and the release of GIIa PLA2 and increased extracellular PLA2 activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA2 protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA2 protein synthesis and release by interleukin-1β-stimulated cells. These results provide direct evidence that p38 MAPK activation was necessary for interleukin-1β-induced synthesis and release of GIIa PLA2 by cardiomyocytes.

Original languageEnglish (US)
Pages (from-to)43842-43849
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number47
DOIs
StatePublished - Nov 23 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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