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J. Biol. Chem., Vol. 283, Issue 24, 16477-16487, June 13, 2008

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

Sailaja Paruchuri, Yongfeng Jiang, Chunli Feng, Sanjeev A. Francis^¶, Jorge Plutzky^¶, and Joshua A. Boyce^||1

From the 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

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), 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 PPAR antagonist GW9662 and to targeted knockdown of PPAR. 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.

Received for publication, July 16, 2007 , and in revised form, April 9, 2008.

^* 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.

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.

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