Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1

• Published in: The Journal of biological chemistry 2004-08, Vol.279 (32), p.33684-33695
• Main Authors: Kamei, Daisuke, Yamakawa, Kiyofumi, Takegoshi, Yui, Mikami-Nakanishi, Maya, Nakatani, Yoshihito, Oh-ishi, Sachiko, Yasui, Hidekazu, Azuma, Yoshiaki, Hirasawa, Noriyasu, Ohuchi, Kazuo, Kawaguchi, Hiroshi, Ishikawa, Yukio, Ishii, Toshiharu, Uematsu, Satoshi, Akira, Shizuo, Murakami, Makoto, Kudo, Ichiro
• Format: Article
• Language: English
• Subjects: Acetic Acid - administration & dosage; Animals; Arthritis, Experimental - enzymology; Arthritis, Experimental - physiopathology; Dinoprostone - biosynthesis; Dinoprostone - physiology; Escherichia coli; Inflammation - physiopathology; Intramolecular Oxidoreductases - deficiency; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - physiology; Lipopolysaccharides - pharmacology; Macrophages, Peritoneal - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microsomes - enzymology; Neovascularization, Pathologic - enzymology; Neovascularization, Pathologic - physiopathology; Nociceptors - physiopathology; Pain - physiopathology; Prostaglandin-E Synthases; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M400199200

We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE2-biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE2, but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE2 production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE2 level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE2 involved in pain hypersensitivity and inflammation.