CD40 ligation protects bronchial epithelium against oxidant-induced caspase-independent cell death
CD40 ligation protects bronchial epithelium against oxidant-induced caspase-independent cell death
复制标题
DOI：
10.1165/rcmb.2005-0433oc
复制
发表时间：
2006-08-01
影响因子：
6.4
通讯作者：
Vignola, Antonio M.
中科院分区：
文献类型：
--
作者：
Merendino, Anna M.;Bucchieri, Fabio;Vignola, Antonio M.
CD 40及其配体调节多效性生物反应，包括细胞增殖、分化和凋亡。在许多炎性肺病中，由环境或内源性氧化剂引起的组织损伤在疾病发病机制中起主要作用。由于上皮屏障是这些氧化剂的主要靶点，因此我们推测，在哮喘中表达增加的CD 40在暴露于氧化剂的支气管上皮细胞凋亡的调节中起作用。使用暴露于氧化应激的16 HBE 140-细胞，我们发现CD 40的连接（由G28-5单克隆抗体诱导）增强了细胞存活并增加了细胞周期的G2/M（DNA合成和有丝分裂之间的间期）中的细胞数量。这与NF-κ B和激活蛋白-1激活以及细胞凋亡抑制剂c-IAP 1表达增加有关。然而，氧化应激诱导的细胞凋亡被认为是半胱天冬酶和钙蛋白酶的独立牵连CD 40连接作为半胱天冬酶的非依赖性细胞死亡的调节。这一点通过CD 40连接阻止线粒体释放和凋亡诱导因子核转位的证明得到证实。总之，我们证明了一个新的作用，CD 40作为一个调节上皮细胞对氧化应激的生存。此外，我们已经确定，为第一次，一个内源性抑制途径的半胱天冬酶非依赖性细胞死亡。
CD40 and its ligand regulate pleiotropic biological responses, including cell proliferation, differentiation, and apoptosis. In many inflammatory lung diseases, tissue damage by environmental or endogenous oxidants plays a major role in disease pathogenesis. As the epithelial barrier is a major target for these oxidants, we postulated that CD40, the expression of which is increased in asthma, plays a role in the regulation of apoptosis of bronchial epithelial cells exposed to oxidants. Using 16HBE 14o- cells exposed to oxidant stress, we found that ligation of CD40 (induced by G28-5 monoclonal antibodies) enhanced cell survival and increased the number of cells in G2/M (interphase between DNA synthesis and mitosis) of the cell cycle. This was associated with NF-kappa B and activator protein-1 activation and increased expression of the inhibitor of apoptosis, c-IAP1. However, oxidant stress-induced apoptosis was found to be caspase- and calpain-independent implicating CD40 ligation as a regulator of caspase-independent cell death. This was confirmed by the demonstration that CD40 ligation prevented mitochondrial release and nuclear translocation of apoptosis inducing factor. In conclusion, we demonstrate a novel role for CD40 as a regulator of epithelial cell survival against oxidant stress. Furthermore, we have identified, for the first time, an endogenous inhibitory pathway of caspase-independent cell death.