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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3263-3270.
Prepublished online as a Blood First Edition Paper on August 10, 2007; DOI 10.1182/blood-2007-07-100453.
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Submitted July 10, 2007
Accepted August 8, 2007
CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene-dependent mitogenic responses of mast cells
Yongfeng Jiang, Laura A. Borrelli, Yoshihide Kanaoka, Brian J. Bacskai, and Joshua A. Boyce*
Department of Medicine, Harvard Medical School, Boston, MA, United States
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
Division of Rheumatology, Immunology & Allergy, Brigham and Women's Hospital, Boston, MA, United States
Department of Pediatrics, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: jboyce{at}rics.bwh.harvard.edu.
Cysteinyl leukotrienes (cys-LTs) induce inflammation through two G protein-coupled receptors (GPCRs), CysLT1 and CysLT2, which are co-expressed by most myeloid cells. Cys-LTs induce proliferation of mast cells (MCs), transactivate c-Kit, and phosphorylate extracellular signal-regulated kinase (ERK). Although MCs express CysLT2, their responses to cys-LTs are blocked by antagonists of CysLT1. We demonstrate that CysLT2 interacts with CysLT1, and that knock-down of CysLT2 increases CysLT1 surface expression and CysLT1-dependent proliferation of cord blood-derived human MCs (hMCs). Cys-LT-mediated responses were absent in MCs from mice lacking CysLT1 receptors, but enhanced by the absence of CysLT2 receptors. CysLT1 and CysLT2 receptors co-localized to the plasma membranes and nuclei of a human MC line, LAD2. Antibody-based fluorescent lifetime imaging microscopy confirmed complexes containing both receptors based on fluorescence energy transfer. Negative regulation of CysLT1-induced mitogenic signaling responses of MCs by CysLT2 demonstrates physiologically relevant functions for GPCR heterodimers on primary cells central to inflammation.
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