p38 MAPK Regulates Group IIa Phospholipase A2Expression in Interleukin-1β-stimulated Rat Neonatal Cardiomyocytes

• Published in: The Journal of biological chemistry 2001-11, Vol.276 (47), p.43842
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M101516200

Group IIa phospholipase A 2 (GIIa PLA 2 ) 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 PLA 2 from cardiomyocytes, and to define the role of p38 MAPK and cytosolic PLA 2 in the regulation of this process. Whereas GIIa PLA 2 mRNA was not identified in untreated cells, exposure to interleukin-1β resulted in the sustained expression of GIIa PLA 2 mRNA. Interleukin-1β also stimulated a progressive increase in cellular and extracellular GIIa PLA 2 protein levels and increased extracellular PLA 2 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 PLA 2 mRNA expression, GIIa PLA 2 protein synthesis, and the release of extracellular PLA 2 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 PLA 2 and increased extracellular PLA 2 activity 3-fold. In contrast, infection with an adenovirus encoding a phosphorylation-resistant MKK6, MKK6(A), did not result in GIIa PLA 2 protein synthesis or release by unstimulated cardiomyocytes. In addition, infection with an adenovirus encoding MKK6(A) abrogated GIIa PLA 2 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 PLA 2 by cardiomyocytes.