Targeted disruption of the leukotriene B(4) receptor in mice reveals its role in inflammation and platelet-activating factor-induced anaphylaxis.
Leukotrienes are derived from arachidonic acid and serve as mediators of inflammation and immediate hypersensitivity. Leukotriene B(4) (LTB(4)) and leukotriene C(4) (LTC(4)) act through G protein-coupled receptors LTB(4) 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 LTB(4) for calcium mobilization or chemotaxis. Additionally, LTB(4) elicited peritoneal neutrophil influx in control but not in BLTR(-/-) mice. Thus, BLTR is the sole receptor for LTB(4)-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.
Haribabu
B
B
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. Boddu001@mc.duke.edu
Verghese
M W
MW
Steeber
D A
DA
Sellars
D D
DD
Bock
C B
CB
Snyderman
R
R
D000707:Anaphylaxis / Q000209:etiology / Q000276:immunology*; D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000276:immunology; D004431:Ear, External / Q000276:immunology; D005260:Female; D018390:Gene Targeting; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D010537:Peritoneum / Q000276:immunology; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000276:immunology*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000276:immunology*; D015054:Zymosan / Q000008:administration & dosage / Q000276:immunology
D018836:Inflammation Mediators; D010972:Platelet Activating Factor; D018102:Receptors, Leukotriene B4; D016718:Arachidonic Acid; D015054:Zymosan