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Leukotriene E4–induced pulmonary inflammation is mediated by the P2Y12 receptor

Leukotriene E4–induced pulmonary inflammation is mediated by the P2Y12 receptor Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC 4 , LTD 4 , and LTE 4 ), only LTE 4 is stable and abundant in vivo. Although LTE 4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT 1 R and CysLT 2 R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y 12 ) receptor is required for LTE 4 -mediated pulmonary inflammation. P2Y 12 receptor expression permits LTE 4 -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D 2 production by LAD2 cells, a human mast cell line. P2Y 12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE 4 but not for direct binding of LTE 4 , suggesting that P2Y 12 complexes with another receptor to recognize LTE 4 . Administration of LTE 4 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 CysLT 1 R and CysLT 2 R but not in mice lacking P2Y 12 receptors. The effects of LTE 4 on P2Y 12 in the airway were abrogated by platelet depletion. Thus, the P2Y 12 receptor is required for proinflammatory actions of the stable abundant mediator LTE 4 and is a novel potential therapeutic target for asthma. Footnotes 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 Submitted: 8 June 2009 Accepted: 16 September 2009 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Experimental Medicine Rockefeller University Press

Leukotriene E4–induced pulmonary inflammation is mediated by the P2Y12 receptor

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Publisher
Rockefeller University Press
Copyright
© 2009 Paruchuri et al.
ISSN
0022-1007
eISSN
1540-9538
DOI
10.1084/jem.20091240
pmid
19822647
Publisher site
See Article on Publisher Site

Abstract

Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC 4 , LTD 4 , and LTE 4 ), only LTE 4 is stable and abundant in vivo. Although LTE 4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT 1 R and CysLT 2 R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y 12 ) receptor is required for LTE 4 -mediated pulmonary inflammation. P2Y 12 receptor expression permits LTE 4 -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D 2 production by LAD2 cells, a human mast cell line. P2Y 12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE 4 but not for direct binding of LTE 4 , suggesting that P2Y 12 complexes with another receptor to recognize LTE 4 . Administration of LTE 4 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 CysLT 1 R and CysLT 2 R but not in mice lacking P2Y 12 receptors. The effects of LTE 4 on P2Y 12 in the airway were abrogated by platelet depletion. Thus, the P2Y 12 receptor is required for proinflammatory actions of the stable abundant mediator LTE 4 and is a novel potential therapeutic target for asthma. Footnotes 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 Submitted: 8 June 2009 Accepted: 16 September 2009

Journal

The Journal of Experimental Medicine – Rockefeller University Press

Published: Oct 26, 2009

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