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¹ Department of Medicine and ² Department of Pediatrics, Harvard Medical School, Boston, MA 02115
³ Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02115
⁴ Portola Pharmaceuticals, San Franciso, CA 94127

CORRESPONDENCE Joshua A. Boyce: jboyce{at}rics.bwh.harvard.edu

Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC₄, LTD₄, and LTE₄), only LTE₄ is stable and abundant in vivo. Although LTE₄ shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT₁R and CysLT₂R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y₁₂) receptor is required for LTE₄-mediated pulmonary inflammation. P2Y₁₂ receptor expression permits LTE₄ -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D₂ production by LAD2 cells, a human mast cell line. P2Y₁₂ receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE₄ but not for direct binding of LTE₄, suggesting that P2Y₁₂ complexes with another receptor to recognize LTE₄. Administration of LTE₄ 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 CysLT₁R and CysLT₂R but not in mice lacking P2Y₁₂ receptors. The effects of LTE₄ on P2Y₁₂ in the airway were abrogated by platelet depletion. Thus, the P2Y₁₂ receptor is required for proinflammatory actions of the stable abundant mediator LTE₄ and is a novel potential therapeutic target for asthma.

Abbreviations used: 2-MesAMP, 2-methylthioadenosine monophosphate; 5-LO, 5-lipoxygenase; ADP, adenosine diphosphate; AERD, aspirin-exacerbated respiratory disease; BAL, bronchoalveolar lavage; cDNA, complementary DNA; CHO, Chinese hamster ovary; COX, cyclooxygenase; Cys-LT, cysteinyl LT; Der f, Dermatophagoides farinae; ERK, extracellular signal-regulated kinase; GPCR, G protein–coupled receptor; HIS, polyhistidine; LT, leukotriene; MC, mast cell; MIP-1β, macrophage inflammatory protein 1β; mRNA, messenger RNA; P2Y, purinergic; PAS, periodic acid–Schiff; PG, prostaglandin; PTX, pertussis toxin; shRNA, short hairpin RNA.

© 2009 Paruchuri et al.
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