Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl 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) C4, which then undergoes extracellular metabolism to LTD4 and LTE4. LTE4, the most stable cys-LT, is only a weak agonist for the defined type 1 and type 2 cys-LT receptors (CysLT1R and CysLT2R, respectively). We had recognized a greater potency for LTE4 than LTC4 or LTD4 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 LTE4 in mice lacking both the CysLT1R and CysLT2R could establish the existence of a separate LTE4 receptor. We now report that the intradermal injection of LTE4 into the ear of mice deficient in both CysLT1R and CysLT2R elicits a vascular leak that exceeds the response to intradermal injection of LTC4 or LTD4, and that this response is inhibited by pretreatment of the mice with pertussis toxin or a Rho kinase inhibitor. LTE4 is ≈64-fold more potent in the CysLT1R/CysLT2R double-deficient mice than in sufficient mice. The administration of a CysLT1R antagonist augmented the permeability response of the CysLT1R/CysLT2R double-deficient mice to LTC4, LTD4, and LTE4. Our findings establish the existence of a third receptor, CysLTER, that responds preferentially to LTE4, the most abundant cys-LT in biologic fluids, and thus reveal a new target for therapeutic intervention.