Leukotriene E(4)–induced pulmonary inflammation is mediated by the P2Y(12) receptor

Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC(4), LTD(4), and LTE(4)), only LTE(4) is stable and abundant in vivo. Although LTE(4) shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT(1)R and CysLT(2)R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y(12)) receptor is required for LTE(4)-mediated pulmonary inflammation. P2Y(12) receptor expression permits LTE(4) -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D(2) production by LAD2 cells, a human mast cell line. P2Y(12) receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE(4) but not for direct binding of LTE(4), suggesting that P2Y(12) complexes with another receptor to recognize LTE(4). Administration of LTE(4) to the airways of sensitized mice potentiates eosinophilia, goblet cell metaplasia, and expression of interleukin-13 in response to low-dose aerosolized allergen. These responses persist in mice lacking both CysLT(1)R and CysLT(2)R but not in mice lacking P2Y(12) receptors. The effects of LTE(4) on P2Y(12) in the airway were abrogated by platelet depletion. Thus, the P2Y(12) receptor is required for proinflammatory actions of the stable abundant mediator LTE(4) and is a novel potential therapeutic target for asthma.