The Journal of Experimental Medicine
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Published online 12 May 2003 doi:10.1084/jem.20030016
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© Rockefeller University Press, 0022-1007/2003/5/1297 $5.00
The Journal of Experimental Medicine, Volume 197, Number 10, 1297-1302

Cytosolic Phospholipase A2{alpha}–deficient Mice Are Resistant to Collagen-induced Arthritis

Martin Hegen1, Linhong Sun1, Naonori Uozumi2, Kazuhiko Kume2, Mary E. Goad1, Cheryl L. Nickerson-Nutter1, Takao Shimizu2 and James D. Clark1

1 Musculoskeletal Sciences, Wyeth Research, Cambridge, MA 02140
2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, and Core Research and Evolutional Science and Technology (CREST), University of Tokyo, Tokyo 113-0033, Japan

Address correspondence to Takao Shimizu, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Phone: 81-3-5802-2925; Fax: 81-3-3813-8732; E-mail: tshimizu{at}m.u-tokyo.ac.jp

Pathogenic mechanisms relevant to rheumatoid arthritis occur in the mouse model of collagen-induced arthritis (CIA). Cytosolic phospholipase A2{alpha} (cPLA2{alpha}) releases arachidonic acid from cell membranes to initiate the production of prostaglandins and leukotrienes. These inflammatory mediators have been implicated in the development of CIA. To test the hypothesis that cPLA2{alpha} plays a key role in the development of CIA, we backcrossed cPLA2{alpha}-deficient mice on the DBA/1LacJ background that is susceptible to CIA. The disease severity scores and the incidence of disease were markedly reduced in cPLA2{alpha}-deficient mice compared with wild-type littermates. At completion of the study, >90% of the wild-type mice had developed disease whereas none of the cPLA2{alpha}-deficient mice had more than one digit inflamed. Furthermore, visual disease scores correlated with severity of disease determined histologically. Pannus formation, articular fibrillation, and ankylosis were all dramatically reduced in the cPLA2{alpha}-deficient mice. Although the disease scores differed significantly between cPLA2{alpha} mutant and wild-type mice, anti-collagen antibody levels were similar in the wild-type mice and mutant littermates. These data demonstrate the critical role of cPLA2{alpha} in the pathogenesis of CIA.

Key Words: inflammation • autoimmunity • rheumatoid arthritis • lipid mediators • gene targeting


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