Leukotriene E4 activates peroxisome proliferator-activated receptor γ and induces prostaglandin D2 generation by human mast cells

Cysteinyl leukotrienes (cys-LTs) are potent inflammatory lipid mediators, of which leukotriene (LT) E-4 is the most stable and abundant in vivo. Although only a weak agonist of established G protein-coupled receptors (GPCRs) for cys-LTs, LTE4 potentiates airway hyper-responsiveness (AHR) by a cyclooxygenase (COX)-dependent mechanism and induces bronchial eosinophilia. We now report that LTE4 activates human mast cells (MCs) by a pathway involving cooperation between an MK571-sensitive GPCR and peroxisome proliferator-activated receptor (PPAR)gamma, a nuclear receptor for dietary lipids. Although LTD4 is more potent than LTE4 for inducing calcium flux by the human MC sarcoma line LAD(2), LTE4 is more potent for inducing proliferation and chemokine generation, and is at least as potent for upregulating COX-2 expression and causing prostaglandin D-2 (PGD(2)) generation. LTE4 caused phosphorylation of extracellular signal-regulated kinase (ERK), p90RSK, and cyclic AMP-regulated-binding protein (CREB). ERK activation in response to LTE4, but not to LTD4, was resistant to inhibitors of phosphoinositol 3-kinase. LTE4-mediated COX-2 induction, PGD2 generation, and ERK phosphorylation were all sensitive to interference by the PPAR gamma antagonist GW9662 and to targeted knockdown of PPAR gamma. Although LTE4-mediated PGD2 production was also sensitive to MK571, an antagonist for the type 1 receptor for cys-LTs (CysLT(1)R), it was resistant to knockdown of this receptor. This LTE4-selective receptor-mediated pathway may explain the unique physiologic responses of human airways to LTE4 in vivo.