Retinoic acid enhances prostaglandin E2 production through increased expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in rat brain microglia

Retinoic acid (RA) is a well‐known antiinflammatory agent. In this study, we show that RA has a dual effect on cyclooxygenase‐2 (COX‐2) expression in inflammatory activated microglia, the resident brain macrophages. After treatment of microglia with LPS or thrombin, COX‐2 expression was induced in two phases, specifically, an initial increase at about 12 hr after stimulation followed by a decrease, and another increase at about 48–72 hr. However, PGE2 and 15d‐PGJ2 were detected at about 12 hr, and the levels continuously increased thereafter. Interestingly, all‐trans retinoic acid (ATRA) suppressed the expression of early‐phase COX‐2 but augmented late‐phase COX‐2 and inhibited iNOS in the whole time sequence. ATRA enhanced PGE2 production but had little effect on 15d‐PGJ2. Moreover, ATRA selectively up‐regulated the expression of a PGE2 synthase, mPGES‐1, but had little effect on the PGD2 synthase, H‐PGDS. The results collectively suggest that ATRA modulates microglial responses to inflammatory stimulators, particularly at the late phase, via enhancement of COX‐2 expression and PGE2 production. © 2008 Wiley‐Liss, Inc.