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Targeted Disruption of the Leukotriene B₄ Receptor in Mice Reveals Its Role in Inflammation and Platelet-activating Factor–induced Anaphylaxis

Correspondence to: Bodduluri Haribabu, Dept. of Medicine, Duke University Medical Center, Box 3680, Durham, NC 27710. Tel:919-684-2280 Fax:919-684-4390 E-mail: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

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