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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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IMMUNOBIOLOGY
CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene–dependent mitogenic responses of mast cells
Yongfeng Jiang1,2,
Laura A. Borrelli3,
Yoshihide Kanaoka1,2,
Brian J. Bacskai3, and
Joshua A. Boyce1,2,4
1 Department of Medicine, Harvard Medical School, Boston, MA;
2 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA;
3 MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, MA;
4 Department of Pediatrics, Harvard Medical School, Boston, MA
Cysteinyl leukotrienes (cys-LTs) induce inflammation through 2 G protein–coupled receptors (GPCRs), CysLT1 and CysLT2, which are coexpressed 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 knockdown 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 colocalized 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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