The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/3/1065/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 6, March 17, 1997 1065-1076

Articles

Role of the 5-Lipoxygenase–activating Protein (FLAP) in Murine Acute Inflammatory Responses

Robert S. Byrum*, Jennifer L. Goulet*, Richard J. Griffiths, and Beverly H. Koller*,{ddagger}

From the * Curriculum in Genetics and Molecular Biology and {ddagger} 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

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.

Address correspondence to Dr. Beverly H. Koller, Department of Medicine, 7007 Thurston-Bowles Bldg., UNC-CH, CB# 7248, Chapel Hill, NC 27599-7248.

1Abbreviations used in this paper: AA, arachidonic acid; DTH, delayed-type hypersensitivity; EIA, enzyme immunoassay; ES, embryonic stem; FLAP, 5-lipoxygenase–activating protein; HETE, hydroxyeicosatetraenoic acid; HSA, human serum albumin; LO, lipoxygenase; LT, leukotriene; MPO, myeloperoxidase; neo, neomysin resistance gene; PAF, platelet-activating factor; PG, prostaglandin; TX, thromboxane.


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