Norozian Farnaz, Kashyap Mohit, Ramirez Carlos D, Patel Neha, Kepley Christopher L, Barnstein Brian O, Ryan John J
Department of Biology, Virginia Commonwealth University, Richmond, VA 23284-2012, USA.
Exp Hematol. 2006 May;34(5):579-87. doi: 10.1016/j.exphem.2006.02.003.
Mast cells are potent effectors of the inflammatory response, playing an important role in atopy, bacterial immunity, and animal models of arthritis, multiple sclerosis, and heart disease. Hence controlling mast cell numbers and responsiveness is essential for preventing inflammatory disease. We demonstrate that the cytokine transforming growth factor (TGF) beta1 is a potent inducer of mast cell apoptosis, a finding that was consistent in cultured mouse bone marrow-derived mast cells, peritoneal mast cells, and human mast cells. Cell death appeared to be caused by TGF-mediated repression of interleukin-3 (IL-3) receptor expression and function, leading to mitochondrial damage and activation of an apoptotic cascade acting via p53 and caspases. Although IL-3 receptor expression was reduced within 1 day of TGFbeta1 stimulation, apoptosis required at least 3 days to occur. This delay in onset is postulated to allow protective mast cell effector functions, protecting the host from infection while preventing the establishment of chronic inflammation. Our data support the theory that TGFbeta1 is an inhibitor of mast cell survival. The widespread expression of TGFbeta1 offers this cytokine as an ideal candidate for control of mast cell homeostasis.
肥大细胞是炎症反应的强效效应细胞，在特应性疾病、细菌免疫以及关节炎、多发性硬化症和心脏病的动物模型中发挥着重要作用。因此，控制肥大细胞数量和反应性对于预防炎症性疾病至关重要。我们证明细胞因子转化生长因子（TGF）β1是肥大细胞凋亡的强效诱导剂，这一发现在培养的小鼠骨髓来源的肥大细胞、腹膜肥大细胞和人肥大细胞中是一致的。细胞死亡似乎是由TGF介导的白细胞介素-3（IL-3）受体表达和功能的抑制引起的，导致线粒体损伤并激活经由p53和半胱天冬酶起作用的凋亡级联反应。尽管在TGFβ1刺激1天内IL-3受体表达就降低了，但凋亡至少需要3天才能发生。这种起始延迟被认为是为了允许肥大细胞发挥保护性效应功能，在防止慢性炎症形成的同时保护宿主免受感染。我们的数据支持TGFβ1是肥大细胞存活抑制剂的理论。TGFβ1的广泛表达使这种细胞因子成为控制肥大细胞稳态的理想候选者。
