Leukotriene E4 activates peroxisome proliferator-activated receptor gamma 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, LTE(4) potentiates airway hyper-responsiveness (AHR) by a cyclooxygenase (COX)-dependent mechanism and induces bronchial eosinophilia. We now report that LTE(4) 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 LTD(4) is more potent than LTE(4) for inducing calcium flux by the human MC sarcoma line LAD2, LTE(4) 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. LTE(4) caused phosphorylation of extracellular signal-regulated kinase (ERK), p90RSK, and cyclic AMP-regulated-binding protein (CREB). ERK activation in response to LTE(4), but not to LTD(4), was resistant to inhibitors of phosphoinositol 3-kinase. LTE(4)-mediated COX-2 induction, PGD(2) generation, and ERK phosphorylation were all sensitive to interference by the PPARgamma antagonist GW9662 and to targeted knockdown of PPARgamma. Although LTE(4)-mediated PGD(2) 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 LTE(4)-selective receptor-mediated pathway may explain the unique physiologic responses of human airways to LTE(4) in vivo.
Paruchuri
Sailaja
S
Department of Medicine, Division of Rheumatology, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Jiang
Yongfeng
Y
Feng
Chunli
C
Francis
Sanjeev A
SA
Plutzky
Jorge
J
Boyce
Joshua A
JA
D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007938:Leukemia / Q000378:metabolism; D017998:Leukotriene D4 / Q000378:metabolism; D017999:Leukotriene E4 / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008407:Mast Cells / Q000166:cytology* / Q000378:metabolism; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000378:metabolism*
D018925:Chemokines; D008055:Lipids; D047495:PPAR gamma; D017998:Leukotriene D4; D017999:Leukotriene E4; D048049:Extracellular Signal-Regulated MAP Kinases; D015230:Prostaglandin D2