Attenuated zymosan-induced peritoneal vascular permeability and IgE dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase

Leukotriene C-4 synthase (LTC4S), the terminal 5-lipoxygenase pathway enzyme that is responsible for the biosynthesis of cysteinyl leukotrienes, has been deleted by targeted gene disruption to define its tissue distribution and integrated pathway function in vitro and in vivo. The LTC4S (-/-) mice developed normally and were fertile. LTC4S activity, assessed by conjugation of leukotriene (LT) A(4) methyl ester with glutathione, was absent from tongue, spleen, and brain and greater than or equal to 90% reduced in lung, stomach, and colon of the LTC4S (-/-) mice. Bone marrow-derived mast cells (BMMC) from the LTC4S (-/-) mice provided no LTC, in response to IgE dependent activation. Exocytosis and the generation of prostaglandin D-2, LTB4, and 5-hydroxyeicosatetraenoic acid by BMMC from LTC4S (-/-) mice and LTC4S (+/+) mice were similar, whereas the degraded product of LTA(4), 6-trans-LTB4, was doubled in BMMC from LTC4S (-/-) mice because of lack of utilization. The zymosan elicited intraperitoneal extravasation of plasma protein and the IgE-mediated passive cutaneous anaphylaxis in the ear were significantly diminished in the LTC4S (-/-) mice. These observations indicate that LTC4S, but not microsomal or cytosolic glutathione S-transferases, is the major LTC4-producing enzyme in tissues and that its integrated function includes mediation of increased vascular permeability in either innate or adaptive immune host inflammatory responses.