Microglia‐specific expression of microsomal prostaglandin E₂ synthase‐1 contributes to lipopolysaccharide‐induced prostaglandin E₂ production

Microsomal prostaglandin E 2 synthase (mPGES)‐1 is an inducible protein recently shown to be an important enzyme in inflammatory prostaglandin E 2 (PGE 2 ) production in some peripheral inflammatory lesions. However, in inflammatory sites in the brain, the induction of mPGES‐1 is poorly understood. In this study, we demonstrated the expression of mPGES‐1 in the brain parenchyma in a lipopolysaccharide (LPS)‐induced inflammation model. A local injection of LPS into the rat substantia nigra led to the induction of mPGES‐1 in activated microglia. In neuron‐glial mixed cultures, mPGES‐1 was co‐induced with cyclooxygenase‐2 (COX‐2) specifically in microglia, but not in astrocytes, oligodendrocytes or neurons. In microglia‐enriched cultures, the induction of mPGES‐1, the activity of PGES and the production of PGE 2 were preceded by the induction of mPGES‐1 mRNA and almost completely inhibited by the synthetic glucocorticoid dexamethasone. The induction of mPGES‐1 and production of PGE 2 were also either attenuated or absent in microglia treated with mPGES‐1 antisense oligonucleotide or microglia from mPGES‐1 knockout (KO) mice, respectively, suggesting the necessity of mPGES‐1 for microglial PGE 2 production. These results suggest that the activation of microglia contributes to PGE 2 production through the concerted de novo synthesis of mPGES‐1 and COX‐2 at sites of inflammation of the brain parenchyma.