P38 MAPK mediates COX-2 gene expression by corticosterone in cardiomyocytes.

Recent work from our laboratory found that corticosteroids induce transcriptional activation of cyclooxygenase-2 (COX-2) gene in cardiomyocytes. Here we report that COX-2 gene promoter mutation studies indicate a role of cAMP response element-binding protein (CREB) in corticosterone-induced COX-2 gene expression. Corticosterone causes activation of p38 MAPK and subsequent CREB phosphorylation at serine 133 in cardiomyocytes. The inhibitors of p38 MAPK, SB202190 and SB203580, block corticosterone from inducing CREB phosphorylation and COX-2 gene expression while dominant-negative p38 MAPK or CREB prevents corticosterone from activating COX-2 promoter. Corticosterone does not induce p38 MAPK activation or COX2 expression in cardiac fibroblasts or HEK293 cells transfected with glucocorticoid receptor, suggesting that p38 MAPK activation is cell specific and necessary for corticosterone-induced COX-2 expression in cardiomyocytes. While glucocorticoid receptor antagonist mifepristone inhibits COX-2 gene induction by corticosterone, mifepristone fails to inhibit p38 MAPK activation or CREB phosphorylation. In contrast, inhibition of p38 MAPK does not prevent corticosterone from activating glucocorticoid receptor. Our data suggest that two parallel signaling pathways, glucocorticoid receptor and p38 MAPK, act in concert to regulate the expression of COX-2 gene in cardiomyocytes.