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Richard J. Griffiths^*, MaryAlice Smith^*, Marsha L. Roach, Jeffrey L. Stock, Ethan J. Stam^*, A.J. Milici^*, Deborah N. Scampoli^*, James D. Eskra^*, Robert S. Byrum, Beverly H. Koller, and John D. McNeish

From the ^* Department of ^*Cancer, Immunology, and Infectious Diseases, Department of Molecular Sciences, Central Research Division, Pfizer, Inc., Groton, Connecticut 06340; and Curriculum in Genetics and Molecular Biology and Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7248

Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.

¹ Abbreviations used in this paper: 5-LO, 5-lipoxygenase; ES, embryonic stem; FLAP, 5-lipoxygenase-activating protein; HETE, hydroxyeicosatetraenoic acid; LTB₄, leukotriene B₄.

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