The Journal of Experimental Medicine
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Published online 7 August 2000.
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© The Rockefeller University Press, 0022-1007/2000/8/433/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 433-438

Brief Definitive Report

Targeted Disruption of the Leukotriene B4Receptor in Mice Reveals Its Role in Inflammation and Platelet-Activating Factor–Induced Anaphylaxis

Bodduluri Haribabua, Margrith W. Verghesea, Douglas A. Steeberb, Dwight D. Sellarsa, Cheryl B. Bockc, and Ralph Snydermana,b

a Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
b Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710
c Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710
Dept. of Medicine, Duke University Medical Center, Box 3680, Durham, NC 27710.919-684-4390919-684-2280

Boddu001{at}mc.duke.edu

Leukotrienes are derived from arachidonic acid and serve as mediators of inflammation and immediate hypersensitivity. Leukotriene B4 (LTB4) and leukotriene C4 (LTC4) act through G protein–coupled receptors LTB4 receptor (BLTR) and Cys-LTR, respectively. To investigate the physiological role of BLTR, we produced mice with a targeted disruption of the BLTR gene. Mice deficient for BLTR (BLTR–/–) developed normally and had no apparent hematopoietic abnormalities. Peritoneal neutrophils from BLTR–/– mice displayed normal responses to the inflammatory mediators C5a and platelet-activating factor (PAF) but did not respond to LTB4 for calcium mobilization or chemotaxis. Additionally, LTB4 elicited peritoneal neutrophil influx in control but not in BLTR–/– mice. Thus, BLTR is the sole receptor for LTB4-induced inflammation in mice. Neutrophil influx in a peritonitis model and acute ear inflammation in response to arachidonic acid was significantly reduced in BLTR–/– mice. In mice, intravenous administration of PAF induces immediate lethal anaphylaxis. Surprisingly, female BLTR–/– mice displayed selective survival (6 of 9; P = 0.002) relative to male (1 of 11) mice of PAF-induced anaphylaxis. These results demonstrate the role of BLTR in leukotriene-mediated acute inflammation and an unexpected sex-related involvement in PAF-induced anaphylaxis.

Key Words: arachidonic acid • neutrophil influx • knock-out • sex-related • chemotaxis

© 2000 The Rockefeller University Press


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