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* Department of Medicine and
Department of Pediatrics, Harvard Medical School and Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital; and
Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02115
Cysteinyl leukotrienes (cys-LTs) induce inflammatory responses through type 1 (CysLT1R) and type 2 (CysLT2R) cys-LT receptors and activate mast cells in vitro. We previously demonstrated that cys-LTs cross-desensitized IL-4-primed primary human mast cells (hMCs) to stimulation with the nucleotide uridine diphosphate (UDP). We now report that hMCs, mouse bone marrow-derived mast cells (mBMMCs), and the human MC line LAD2 all express UDP-selective P2Y6 receptors that cooperate with CysLT1R to promote cell survival and chemokine generation by a pathway involving reciprocal ligand-mediated cross-talk. Leukotriene (LT) D4, the most potent CysLT1R ligand, and UDP both induced phosphorylation of ERK and prolonged the survival of cytokine-starved hMCs and mBMMCs. ERK activation and cytoprotection in response to either ligand were attenuated by treatment of the cells with a selective P2Y6 receptor antagonist (MRS2578), which did not interfere with signaling through recombinant CysLT1R. Surprisingly, both UDP and LTD4-mediated ERK activation and cytoprotection were absent in mBMMCs lacking CysLT1R and the biosynthetic enzyme LTC4 synthase, implying a requirement for a cys-LT-mediated autocrine loop. In IL-4-primed LAD2 cells, LTD4 induced the generation of MIP-1β, a response blocked by short hairpin RNA-mediated knockdown of CysLT1R or P2Y6 receptors, but not of CysLT2R. Thus, CysLT1R and P2Y6 receptors, which are coexpressed on many cell types of innate immunity, reciprocally amplify one another’s function in mast cells through endogenous ligands.
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1 This work was supported by National Institutes of Health Grants AI-48802, AI-52353, AI-31599, HL-36110, and EB-00768 and by grants from the Charles Dana Foundation and the Vinik Family Fund for Research in Allergic Diseases.
2 Address correspondence and reprint requests to Dr. Joshua A. Boyce, Brigham and Women’s Hospital, Harvard Medical School, One Jimmy Fund Way, Smith Building Room 626, Boston, MA 02115. E-mail: jboyce{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: LT, leukotriene; cys-LT, cysteinyl LT; CysLT1R, type 1 receptor for cys-LT; CysLT2R, type 2 receptor for cys-LT; Fc
RI, high-affinity Fc receptor for IgE; FLAP, 5-lipoxygenase activating protein; GPCR, G protein-coupled receptor; hMC, cord blood-derived human MC; LTC4S, LTC4 synthase; MC, mast cell; P2Y, purinergic; SCF, stem cell factor; shRNA, short hairpin RNA; MC, mast cell; UDP, uridine diphosphate; mBMMC, mouse bone marrow-derived MC; FLIM, fluorescence lifetime imaging microscopy; MFI, mean fluorescence intensity; FRET, fluorescence resonance energy transfer; CHO, Chinese hamster ovary.
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  S. Paruchuri, H. Tashimo, C. Feng, A. Maekawa, W. Xing, Y. Jiang, Y. Kanaoka, P. Conley, and J. A. Boyce Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor J. Exp. Med., October 26, 2009; 206(11): 2543 - 2555. [Abstract] [Full Text] [PDF]
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