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From the * Curriculum in Genetics and Molecular Biology and Leukotrienes are potent inflammatory mediators synthesized from arachidonic acid (AA) predominately by cells of myeloid origin. The synthesis of these lipids is believed to be dependent
not only on the expression of the enzyme 5-lipoxygenase (5-LO), which catalyzes the first steps
in the synthesis of leukotrienes, but also on expression of a nuclear 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
FLAP 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 comparing inflammatory reactions in FLAP-deficient mice and in normal controls revealed that FLAP plays a role in a subset of these reactions. Although 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 increased resistance to platelet-activating factor-induced shock compared
to controls. Also, edema associated with Zymosan A-induced peritonitis was markedly reduced
in animals lacking FLAP. To determine whether these differences relate solely to a deficit in
leukotriene production, or whether they reflect an additional role for FLAP in inflammation,
we compared the FLAP-deficient mice to 5-LO-deficient animals. Evaluation of mice lacking
FLAP and 5-LO indicated that production of leukotrienes during inflammatory responses is
dependent upon the availability of FLAP and did not support additional functions for FLAP
beyond its role in leukotriene production.
Department of Medicine, University of
North Carolina, Chapel Hill, North Carolina 27599-7248; and Department of Cancer,
Immunology and Infectious Diseases, Central Research Division, Pfizer Inc., Groton, Connecticut
06340
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