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J. Biol. Chem., Vol. 279, Issue 32, 33684-33695, August 6, 2004

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

Daisuke Kamei, Kiyofumi Yamakawa¶, Yui Takegoshi, Maya Mikami-Nakanishi, Yoshihito Nakatani, Sachiko Oh-ishi, Hidekazu Yasui||, Yoshiaki Azuma||, Noriyasu Hirasawa**, Kazuo Ohuchi**, Hiroshi Kawaguchi¶, Yukio Ishikawa, Toshiharu Ishii, Satoshi Uematsu, Shizuo Akira, Makoto Murakami, and Ichiro Kudo¶¶

From the Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, the ^¶Department of Orthopedic Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, ^||Pharmaceutical Discovery Research Laboratories, the Institute for Biomedical Researh, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512, the ^**Laboratory of Pathophysiological Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, the Department of Pathology, Toho University, School of Medicine, 5-21-16 Omori-Nishi, Ohta-ku, Tokyo 143-8540, and the Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan

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.

Received for publication, January 8, 2004 , and in revised form, April 22, 2004.

^* This work was supported by grants-in aid for scientific research from the Ministry of Education, Science, Culture, Sports, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors equally contributed to this work.

^¶¶ To whom correspondence should be addressed. Tel.: 81-3-3784-8196; Fax: 81-3-3784-8245; E-mail: kudo{at}pharm.showa-u.ac.jp.

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