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

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.