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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 Pathway¹

Satoshi Uematsu^*,, Makoto Matsumoto^*, Kiyoshi Takeda^*, and Shizuo Akira^2,*,

^* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and Solution-Oriented Research for Science and Technology of Japan Science and Technology Corp., Suita, Osaka, Japan

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- 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.