Functional Recognition Of A Distinct Receptor Preferential For Leukotriene E_4 In Mice Lacking The Cvsteinyl Leukotriene 1 And 2 Receptors

摘要

The cysteinyl leukotrienes (cys-LTs) are a family of potent lipid mediators of inflammation derived from arachidonic acid. Activation of certain cell types results in the biosynthesis and export of , leukotriene (LT) C_4, which then undergoes extracellular metabo-lism to LTD_4 and LTE_4. LTE_4, the most stable cys-LT, is only a weak agonist for the defined type 1 and type 2 cys-LT receptors (CysLT_1R and CysLT_2R, respectively). We had recognized a greater potency for LTE_4 than LTC_4 or LTD_4 in constricting guinea pig trachea in vitro and comparable activity in eliciting a cutaneous wheal and flare response in humans. Thus, we hypothesized that a vascular permeability response to LTE_4 in mice lacking both the CysLT_1R and CysLT_2R could establish the existence of a separate LTE_4 receptor. We now report that the intradermal injection of LTE_4 into the ear of mice deficient in both CysLT_1R and CysLT_2R elicits a vascular leak that exceeds the response to intradermal injection of LTC_4 or LTD_4, and that this response is inhibited by pretreatment of the mice with pertussis toxin or a Rho kinase inhibitor. LTE_4 is ≈64-fold more potent in the CysLT_1R/CysLT_2R double-deficient mice than in sufficient mice. The administration of a CysLT_1R antagonist augmented the permeability response of the CysLT_1R/CysLT_2R double-deficient mice to LTC_4, LTD_4, and LTE_4. Our findings establish the existence of a third receptor, CysLT_ER, that responds preferentially to LTE_4, the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention.