Jiang Yongfeng, Kanaoka Yoshihide, Feng Chunl, Nocka Karl, Rao Sudhir, Boyce Joshua A
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2006 Sep 1;177(5):2755-9. doi: 10.4049/jimmunol.177.5.2755.
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.
上皮表面的反应性肥大细胞增多症（RM）是变应性疾病中与Th2相关的一个持续特征。在缺乏白三烯（LT）C4合酶（LTC4S）的小鼠中不会发生RM，LTC4S是半胱氨酰白三烯（cys-LT）产生所必需的。我们现在报告，由肥大细胞（MC）诱导LTC4S表达的白细胞介素-4（IL-4），需要cys-LTs、cys-LT 1型受体（CysLT1）和Gi蛋白来促进MC增殖。白三烯D4（LTD4，10 - 1000 nM）以CysLT1依赖、百日咳毒素敏感的方式增强人MC的增殖。LTD4诱导的细胞外信号调节激酶（ERK）磷酸化需要c-kit的反式激活。IL-4驱动的有丝分裂同样对百日咳毒素或CysLT1选择性拮抗剂敏感，并因白三烯合成抑制剂的处理而减弱。缺乏LTC4S或CysLT1的小鼠MC显示IL-4诱导的有丝分裂显著减少。因此，IL-4部分通过诱导LTC4S和cys-LT的产生来诱导增殖，这导致CysLT1在RM中反式激活c-kit。
