ROLE OF THE 5-LIPOXYGENASE-ACTIVATING PROTEIN (FLAP) IN MURINE ACUTE INFLAMMATORY RESPONSES

Leukotrienes are potent inflammatory mediators synthesized from arachi donic acid (AA) predominately by cells of myeloid origin. The synthesi s of these lipids is believed to be dependent not only on the expressi on of the enzyme 5-lipoxygenase (5-LO), which catalyzes the first step s in the synthesis of leukotrienes, but also on expression of a nuclea r membrane protein termed the 5-LO-activating protein (FLAP). To study the relationship of these two proteins in mediating the production of leukotrienes in vivo and to determine whether the membrane protein FL AP has additional functions in various inflammatory processes, we have generated a mouse line deficient in this protein FLAP-deficient mice develop normally and are healthy. However, an array of assays comparin g inflammatory reactions in FLAP-deficient mice and in normal controls revealed that FLAP plays a role in a subset of these reactions. Altho ugh examination of DTH and IgE-mediated passive anaphylaxis showed no difference between wild-type and FLAP-deficient animals, mice without FLAP possessed a blunted inflammatory response to topical AA and had i ncreased resistance to platelet-activating factor-induced shock compar ed to controls. Also, edema associated with Zymosan A-induced peritoni tis was markedly reduced in animals lacking FLAP. To determine whether these differences relate solely to a deficit in leukotriene productio n, or whether they reflect an additional role for FLAP in inflammation , we compared the FLAP-deficient mice to 5-LO-deficient animals. Evalu ation of mice lacking FLAP and 5-LO indicated that production of leuko trienes during inflammatory responses is dependent upon the availabili ty of FLAP and did not support additional functions for FLAP beyond it s role in leukotriene production.