c-Jun N-terminal kinase-mediated stabilization of microsomal prostaglandin E2 synthase-1 mRNA regulates delayed microsomal prostaglandin E2 synthase-1 expression and prostaglandin E2 biosynthesis by cardiomyocytes.

Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2), a key proinflammatory mediator. The purpose of this study was to elucidate the regulation of mPGES-1 mRNA expression in cardiomyocytes, define the role of JNK enzymes in this process, and characterize the role of mPGES-1 in cardiomyocyte PGE(2) biosynthesis. In neonatal cardiomyocytes, interleukin-1beta and lipopolysaccharide (LPS) both stimulated mPGES-1 mRNA expression and increased mPGES-1 mRNA stability and protein synthesis but failed to increase mPGES-1 mRNA transcription. Treatment with the JNK1/2 inhibitor, SP600125, abrogated the increases in mPGES-1 mRNA stability, mPGES-1 protein synthesis, and PGE(2) release induced by interleukin-1beta or LPS. mPGES-1 protein synthesis was observed in LPS-stimulated neonatal cardiomyocytes from jnk1(-/-) or jnk2(-/-) mice. In contrast, infection of jnk1(-/-) cardiomyocytes with an adenovirus encoding phosphorylation-resistant JNK2 (ad-JNK2-DN), or of jnk2(-/-) cardiomyocytes with ad-JNK1-DN, significantly decreased LPS-stimulated mPGES-1 protein synthesis. Similarly, co-infection with ad-JNK1-DN and ad-JNK2-DN attenuated LPS-stimulated mPGES-1 protein synthesis in cardiomyocytes from wild type mice. Targeted deletion of the gene encoding mPGES-1 led to a 3.2-fold decrease in LPS-stimulated PGE(2) release by cardiomyocytes in comparison with wild type cells but had no effect on COX-1, COX-2, mPGES-2, or cytosolic PGES mRNA levels. These studies provide direct evidence that mPGES-1 mRNA levels in cardiomyocytes are augmented by stabilization of mPGES-1 mRNA, that JNK1 or JNK2 can participate in the regulation of mPGES-1 protein synthesis in these cells, and that mPGES-1 catalyzes the majority of LPS-induced PGE(2) biosynthesis by cardiomyocytes.