Lipopolysaccharide-Dependent Prostaglandin E2 Production Is Regulated by the Glutathione-Dependent Prostaglandin E2 Synthase Gene Induced by the Toll-Like Receptor 4/MyD88/NF-IL6 Pathway

Abstract

Macrophages produce a large amount of PGE2 during inflammation. This lipid mediator modulates various immune responses. PGE2 acts on macrophages and inhibits production of cytokines such as TNF-α and IL-12. Membrane-bound glutathione-dependent PGE2 synthase (mPGES) has been shown to be a terminal enzyme of the cyclooxygenase-2-mediated PGE2 biosynthesis. Here we identified mPGES as a molecule that is induced by LPS in macrophages. The expression of mPGES was not induced by LPS in mice lacking Toll-like receptor 4 or MyD88. Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES nor biosynthesis of PGE2 in response to LPS, indicating that mPGES expression in response to LPS is regulated by a Toll-like receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated mPGES-deficient mice and investigated the role of mPGES in vivo. The mice showed no augmentation of the PGE2 production in response to LPS. However, they were not impaired in the LPS-induced production of inflammatory cytokines and showed normal response to the LPS-induced shock. Thus, mPGES is critically involved in the biosynthesis of PGE2 induced by LPS, but is dispensable for the modulation of inflammatory responses.