Kim Hoe Suk, Loughran Patricia A, Kim Peter K, Billiar Timothy R, Zuckerbraun Brian S
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Biochem Biophys Res Commun. 2006 Jun 16;344(4):1172-8. doi: 10.1016/j.bbrc.2006.03.180. Epub 2006 Apr 6.
We have previously shown that carbon monoxide (CO) (250 ppm) prevented tumor necrosis factor-alpha (TNFalpha)-induced apoptosis and activated the transcription factor NF-kappaB in hepatocytes both in vivo and in vitro. These studies were conducted to further determine the mechanisms by which CO suppresses apoptotic signaling in TNFalpha (10 ng/ml) and Actinomycin D (ActD, 200 ng/ml)-treated hepatocytes. Consistent with our previous findings, CO protected against TNFalpha/ActD-induced cell death, which is in part dependent on NF-kappaB activation. This was associated with a reduction in mitochondrial damage, a decrease in cytochrome c release, and an inhibition of translocation of Bcl proteins to mitochondria. In conjugation with inhibition of these mitochondrial events, CO also suppressed caspases-8 and -3 cleavage in response to TNFalpha/ActD. Inhibition of NF-kappaB activation resulted in diminished CO-induced cFLIP expression and increased caspase-8 cleavage from cells treated with TNFalpha/ActD. These data indicate that CO interferes with apoptotic signaling at a proximal step.
我们之前已经表明，一氧化碳（CO）（250 ppm）在体内和体外均可预防肿瘤坏死因子-α（TNFα）诱导的肝细胞凋亡，并激活转录因子NF-κB。进行这些研究是为了进一步确定CO抑制TNFα（10 ng/ml）和放线菌素D（ActD，200 ng/ml）处理的肝细胞中凋亡信号传导的机制。与我们之前的发现一致，CO可保护细胞免受TNFα/ActD诱导的细胞死亡，这部分依赖于NF-κB的激活。这与线粒体损伤的减少、细胞色素c释放的减少以及Bcl蛋白向线粒体转位的抑制有关。与这些线粒体事件的抑制相结合，CO还可抑制TNFα/ActD诱导的caspases-8和-3的切割。NF-κB激活的抑制导致CO诱导的cFLIP表达减少，并增加TNFα/ActD处理细胞中caspase-8的切割。这些数据表明，CO在近端步骤干扰凋亡信号传导。
