Song Ruiping, Zhou Zhihong, Kim Peter K M, Shapiro Richard A, Liu Fang, Ferran Christiane, Choi Augustine M K, Otterbein Leo E
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
J Biol Chem. 2004 Oct 22;279(43):44327-34. doi: 10.1074/jbc.M406105200. Epub 2004 Jul 27.
A properly functioning immune system is dependent on programmed cell death/apoptosis at virtually every stage of lymphocyte development and activity. Carbon monoxide (CO), an enzymatic product of heme oxyenase-1, has been shown to possess anti-apoptotic effects in a number of different model systems. The purpose of the present study was to expand on this knowledge to determine the role of CO in the well established model of Fas/CD95-induced apoptosis in Jurkat cells, and to determine the mechanism by which CO can modulate T-cell apoptosis. Exposure of Jurkat cells to CO resulted in augmentation in Fas/CD95-induced apoptosis, which correlated with CO-induced up-regulation of the pro-apoptotic protein FADD as well as activation of caspase-8, -9, and -3 while simultaneously down-regulating the anti-apoptotic protein BCL-2. These effects of CO were lost with overexpression of the small interfering RNA of FADD. CO, as demonstrated previously in endothelial cells, was also anti-apoptotic in Jurkat cells against tumor necrosis factor and etoposide. We further demonstrate that this pro-apoptotic effect of CO was independent of reactive oxygen species production and involved inhibition in Fas/CD95-induced activation of the pro-survival ERK MAPK. We conclude that in contrast to other studies showing the anti-apoptotic effects of CO, Fas/CD95-induced cell death in Jurkat cells is augmented by exposure to CO and that this occurs in part via inhibition in the activation of ERK MAPK. These data begin to elucidate specific differences with regard to the effects of CO and cell death pathways and provide important and valuable insight into potential mechanisms of action.
一个功能正常的免疫系统在淋巴细胞发育和活动的几乎每个阶段都依赖于程序性细胞死亡/凋亡。一氧化碳（CO）是血红素加氧酶-1的酶促产物，已被证明在许多不同的模型系统中具有抗凋亡作用。本研究的目的是扩展这方面的知识，以确定CO在已建立的Jurkat细胞中Fas/CD95诱导的凋亡模型中的作用，并确定CO调节T细胞凋亡的机制。将Jurkat细胞暴露于CO导致Fas/CD95诱导的凋亡增加，这与CO诱导的促凋亡蛋白FADD上调以及半胱天冬酶-8、-9和-3的激活相关，同时下调抗凋亡蛋白BCL-2。FADD小干扰RNA的过表达使CO的这些作用消失。正如先前在内皮细胞中所证明的，CO在Jurkat细胞中对肿瘤坏死因子和依托泊苷也具有抗凋亡作用。我们进一步证明，CO的这种促凋亡作用独立于活性氧的产生，并且涉及对Fas/CD95诱导的促存活ERK MAPK激活的抑制。我们得出结论，与其他显示CO具有抗凋亡作用的研究相反，暴露于CO会增加Jurkat细胞中Fas/CD95诱导的细胞死亡，并且这部分是通过抑制ERK MAPK的激活而发生的。这些数据开始阐明关于CO作用和细胞死亡途径的具体差异，并为潜在的作用机制提供重要且有价值的见解。
