Microsomal prostaglandin E synthase-1 induced by hemoglobin in microglia contributes to inflammation and neuronal death

We have previously demonstrated that microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, aggravates brain inflammation and neurotoxicity in collagenase-induced intracerebral hemorrhage (ICH) mice. In this study, we investigated the role of microglial mPGES-1 in the hemoglobin (Hb)-induced inflammatory responses and neurotoxicity in vitro. At first, we investigated the effect of Hb on mPGES-1 induction and PGE2 production using neuronal cell line, SH-SY5Y cells and microglial cell line, BV-2 cells. mPGES-1 was significantly induced by Hb in BV-2 cells, but not in SH-SY5Y cells. PGE2 production after Hb exposure was increased in BV-2 cells but decreased in SH-SY5Ycells. Therefore, we next investigated the role of microglial mPGES-1 in Hb responses using primary microglial culture obtained from Wild-type (WT) and mPGES-1 knock out (KO) mice. Hb significantly increased PGE2 production in WT microglia, but not in mPGES-1 KO microglia. The Hb-induced mRNA expressions of TNF-α and IL-1β in mPGES-1 KO microglia were significantly less than those in WT microglia. Furthermore, Hb-induced neurotoxicity of cortical neurons cocultured with mPGES-1 KO microglia was less severe than that cocultured with WT microglia. These results suggest that microglial mPGES-1 contributes to neuronal death after ICH through PGE2 production and regulation of inflammatory cytokines. Thus, mPGES-1 may be a promising therapeutic target for the treatment of ICH.