title: Reduced pain hypersensitivity and inflammation in mice lacking microsomal prostaglandin e synthase-1.
abstract: 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.
authors.affiliation: Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamei
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamakawa
authors.forename: Yui
authors.initials: Y
authors.lastname: Takegoshi
authors.forename: Maya
authors.initials: M
authors.lastname: Mikami-Nakanishi
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Sachiko
authors.initials: S
authors.lastname: Oh-Ishi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Yasui
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Azuma
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Hirasawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ishii
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kudo
mesh_terms: D019342:Acetic Acid / Q000008:administration & dosage; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology / Q000503:physiopathology; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D004926:Escherichia coli; D007249:Inflammation / Q000503:physiopathology*; D019746:Intramolecular Oxidoreductases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000503:physiopathology; D009619:Nociceptors / Q000503:physiopathology; D010146:Pain / Q000503:physiopathology*; D000071876:Prostaglandin-E Synthases; D014162:Transfection
chemical_list: D008070:Lipopolysaccharides; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D019342:Acetic Acid