p38 MAPK regulates group IIa phospholipase A(2) expression in interleukin-1 beta-stimulated rat neonatal cardiomyocytes

Group IIa phospholipase A(2) (GII(a) PLA(2)) is released by some cells in r esponse to interleukin-1 beta. The purpose of this study was to determine w hether interieukin-1 beta would stimulate the Synthesis and release of GIIa PLA2 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-1 beta resulted in the sustained expression of GIIa PLA(2) mRNA. Interleukin-1 beta also stimu lated a progressive increase in cellular and extracellular GIIa PLA(2) prot ein levels and increased extracellular PLA(2) activity 70-fold. In addition , interleukin-1 beta stimulated the p38 MAPK-dependent activation of the do wnstream MAPK-activated protein kinase, MAPKAP-K2. Treatment with the p38 M APK inhibitor, SB202190, decreased interleukin-1 beta stimulated,, mRNA exp ression, GIIa MAPKAP-K2 activity, GIIa PLA, PLA(2) protein synthesis, and t he release of extracellular PLA(2) activity. Infection with an adenovirus e ncoding a constitutively active form of MKK6, MKK6(Glu), which selectively phosphorylates p38 MAPK, induced cellular GIIa PLA protein synthesis and th e release of GIIa PLA(2) and increased extracellular PLA(2) activity 3-fold . In contrast, infection with an adenovirus encoding a phosphorylation-resi stant MKK6, MKKK6(A), did not result in GIIa PLA(2) protein synthesis or re lease by unstimulated cardiomyocytes. In addition, infection with an adenov irus encoding MKK6(A) abrogated GIIa PLA(2) protein synthesis and release b y interleukin-1 beta -stimulated cells. These results provide direct eviden ce that p38 MAPK activation was necessary for interleukin-1 beta -induced s ynthesis and release of GIIa PLA(2) by cardiomyocytes.