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CUTTING EDGE |
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* Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA 02115;
Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115;
Partners Asthma Center, Boston, MA 02115; and
UCB Pharma, Cambridge, MA 02140
Reactive mastocytosis (RM) in epithelial surfaces is a consistent Th2-associated feature of allergic disease. RM fails to develop in mice lacking leukotriene (LT) C4 synthase (LTC4S), which is required for cysteinyl leukotriene (cys-LT) production. We now report that IL-4, which induces LTC4S expression by mast cells (MCs), requires cys-LTs, the cys-LT type 1 receptor (CysLT1), and Gi proteins to promote MC proliferation. LTD4 (10–1000 nM) enhanced proliferation of human MCs in a CysLT1-dependent, pertussis toxin-sensitive manner. LTD4-induced phosphorylation of ERK required transactivation of c-kit. IL-4-driven comitogenesis was likewise sensitive to pertussis toxin or a CysLT1-selective antagonist and was attenuated by treatment with leukotriene synthesis inhibitors. Mouse MCs lacking LTC4S or CysLT1 showed substantially diminished IL-4-induced comitogenesis. Thus, IL-4 induces proliferation in part by inducing LTC4S and cys-LT generation, which causes CysLT1 to transactivate c-kit in RM.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI-48802, AI-52353, AI-31599, and HL-36110 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, One Jimmy Fund Way, Smith Building, Room 626, Boston, MA 02115. E-mail address: jboyce{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: MC, mast cell; hMC, human MC; MCp, mast cell progenitor; mBMMC, mouse bone marrow-derived MC; LT, leukotriene; cys-LT, cysteinyl LT; CysLT1, type 1 receptor for cys-LTs; LTC4S, LTC4 synthase; PTX, pertussis toxin; RM, reactive mastocytosis; RTK, receptor tyrosine kinase; SCF, stem cell factor.
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