Yeatman C F, Jacobs-Helber S M, Mirmonsef P, Gillespie S R, Bouton L A, Collins H A, Sawyer S T, Shelburne C P, Ryan J J
Department of Biology, Virginia Commonwealth University, Richmond, Virginia 23284, USA.
J Exp Med. 2000 Oct 16;192(8):1093-103. doi: 10.1084/jem.192.8.1093.
Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)-antigen interactions is promoted by T helper cell type 2 (Th2) cytokines and leads to the sequelae of allergic disease. We now report a mechanism by which Th2 cytokines can regulate mast cell survival. Specifically, we find that interleukin (IL)-4 and IL-10 induce apoptosis in IL-3-dependent bone marrow-derived mast cells and peritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of transcription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl-x(L) and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated death. Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3-independent mastocytomas and mast cell lines were resistant to apoptosis induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine-mediated homeostasis whereby these cytokines both elicit and limit allergic responses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.
肥大细胞存在于全身的结缔组织和黏膜组织中。通过2型辅助性T细胞（Th2）细胞因子促进其经由免疫球蛋白E（IgE）-抗原相互作用而激活，并导致过敏性疾病的一系列后果。我们现在报告一种Th2细胞因子可调节肥大细胞存活的机制。具体而言，我们发现白细胞介素（IL）-4和IL-10可诱导依赖IL-3的骨髓来源肥大细胞和腹膜肥大细胞发生凋亡。此过程需要IL-3、IL-4和IL-10共刺激6天，以及信号转导和转录激活因子6（Stat6）的表达。凋亡与bcl-x(L)和bcl-2表达降低相关。虽然此过程独立于Fas途径发生，但在IL-3+IL-4+IL-10中培养可使肥大细胞对Fas介导的死亡高度敏感。此外，我们发现IgE交联或用干细胞因子刺激可增强IL-4和IL-10的凋亡能力。最后，不依赖IL-3的肥大细胞瘤和肥大细胞系对IL-3+IL-4+IL-10诱导的凋亡具有抗性。这些数据提供了Th2细胞因子介导的稳态的证据，即这些细胞因子既能引发又能限制过敏反应。该途径的失调可能在过敏性疾病和肥大细胞肿瘤存活中起作用。
