Leukotriene E4 Activates Peroxisome Proliferator-activated Receptor γ and Induces Prostaglandin D2 Generation by Human Mast Cells

doi:10.1074/jbc.M705822200

Leukotriene E₄ Activates Peroxisome Proliferator-activated Receptor γ and Induces Prostaglandin D₂ Generation by Human Mast Cells*

Departments of ^‡Medicine and ^∥Pediatrics, Harvard Medical School, and the Divisions of ^§Rheumatology, Immunology, and Allergy and ^¶Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115

1 To whom correspondence should be addressed: Brigham and Women's Hospital, One Jimmy Fund Way, Smith Bldg. Rm. 626, Boston, MA 02115. Tel.: 617-525-1261; Fax: 617-525-1260; E-mail: jboyce{at}rics.bwh.harvard.edu.

Abstract

Cysteinyl leukotrienes (cys-LTs) are potent inflammatory lipid mediators, of which leukotriene (LT) E₄ 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)γ, a nuclear receptor for dietary lipids. Although LTD₄ is more potent than LTE₄ for inducing calcium flux by the human MC sarcoma line LAD2, LTE₄ is more potent for inducing proliferation and chemokine generation, and is at least as potent for upregulating COX-2 expression and causing prostaglandin D₂ (PGD₂) 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 PPARγ antagonist GW9662 and to targeted knockdown of PPARγ. Although LTE₄-mediated PGD₂ production was also sensitive to MK571, an antagonist for the type 1 receptor for cys-LTs (CysLT₁R), 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.

Footnotes

↵2 The abbreviations used are: cys-LT, cysteinyl leukotriene; Ab, antibody; 5-LO, 5 lipoxygenase; AERD, aspirin-exacerbated respiratory disease; AHR, airway hyper-responsiveness; BAL, bronchoalveolar lavage; COX, cyclooxygenase; CREB, cyclic AMP-regulated-binding protein; CysLT₁R, type 1 receptor for cys-LTs; CysLT₂R, type 2 receptor for cys-LTs; ERK, extracellular signal-regulated kinase; FACS, fluorescence-activated cell sorting; FcϵRI, high-affinity Fc receptor for IgE; FLAP, 5-lipoxygenase activating protein; GPCR, G protein-coupled receptor; hMC, cord blood-derived human MC; IL, interleukin; LBD, ligand binding domain; LC-MS, liquid chromatography-mass spectroscopy; LT, leukotriene; LTC₄S, leukotriene C₄ synthase; MC, mast cell; MEK, mitogen-activated protein kinase kinase; MIP-1β, macrophage inflammatory protein 1β; MOX, methoxylamine; p90RSK, 90-kDa ribosomal S6 kinase; PGD₂, prostaglandin D₂; PGDS, PGD₂ synthase; PI3K, phosphatidylinositol 3-kinase; PLA₂, phospholipase A₂; PPAR, peroxisome proliferator-activated receptor; PTX, pertussis toxin; RT, reverse transcriptase; SCF, stem cell factor; shRNA, short hairpin RNA; siRNA, small interfering RNA; TNF-α, tumor necrosis factor-α.
↵3 Y. Kanaoka, unpublished data.
↵* This work was supported, in whole or in part, by National Institutes of Health Grants AI-48802, AI-52353, AI-31599, HL-36110, and EB-00768. This work was also supported by grants from the Charles Dana Foundation, and the Vinik Family Fund for Research in Allergic Diseases. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received July 16, 2007.
- Revision received April 9, 2008.
The American Society for Biochemistry and Molecular Biology, Inc.