COLLAGEN-INDUCED ARTHRITIS IS REDUCED IN 5-LIPOXYGENASE-ACTIVATING PROTEIN-DEFICIENT MICE

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 (E S) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targetin g in ES cells develop and sow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, wh ereas they produce substantial amounts of prostaglandins. The inflamma tory response to zymosan is reduced in FLAP-deficient mice. The severi ty of collagen-induced arthritis in the FLAP-deficient mice was substa ntially 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. Th ese data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.