Liu Bei, Sun Ruili, Luo Hongbo, Liu Xueting, Jiang Manli, Yuan Chuang, Yang Li, Hu Jinyue
Medical Research Center, Changsha Central Hospital, Changsha, China; Department of Pathology, Affiliated Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China.
Department of Laboratory Medicine, XinXiang Medical University, XinXiang, China.
Immunobiology. 2017 Feb;222(2):198-205. doi: 10.1016/j.imbio.2016.10.002. Epub 2016 Oct 4.
Our previous study showed that TLR3 induces apoptosis via both death receptors and mitochondial in human endothelial cells. We report here that the activation of TLR4 induced dose- and time-dependent cell death in moncytic THP-1 cells. LPS treatment of THP-1 cells induced the activation of both caspase 8 and 9, suggesting the involvement of intrinsic and extrinsic apoptosis pathways. TNFα was induced by TLR4 activation at both mRNA and protein levels, but its neutralization did not down-regulated TLR4-induced cell death. TLR4 activation also induced the up-regulation of TRAIL and its receptors DR4 and DR5, and the neutralization of TRAIL ameliorated TLR4 induced apoptosis, suggesting the involvement of TRAIL and its receptors DR4 and DR5 in LPS-induced cell death. Meanwhile, LPS treatment down-regulated the expression of FLICE inhibitory protein (FLIP), a suppressor of death receptor-induced cell death. In addition, TLR4 activation down-regulated the anti-apoptotic protein bcl-2, and up-regulated the pro-apoptotic proteins Noxa and Puma, suggesting that mitochondrial apoptotic pathway was also involved in LPS-induced cell death. Furthermore, we found that TAP63α might confer to the activation of intrinsic and extrinsic apoptotic pathways. The treatment of THP-1 cells with LPS induced the translocation of TAP63α from cytoplasm to nucleus. Taken together, our study suggested that both death receptors and mitochondial were involved in TLR4-induced cell death, and TAP63α may be a target for the prevention of LPS-induced cell death.
我们之前的研究表明，在人内皮细胞中，Toll样受体3（TLR3）通过死亡受体和线粒体诱导细胞凋亡。我们在此报告，Toll样受体4（TLR4）的激活在单核细胞THP-1细胞中诱导剂量和时间依赖性的细胞死亡。用脂多糖（LPS）处理THP-1细胞可诱导半胱天冬酶8和9的激活，提示内源性和外源性凋亡途径均参与其中。TLR4激活在mRNA和蛋白质水平均诱导肿瘤坏死因子α（TNFα）产生，但其抗体中和并不能下调TLR4诱导的细胞死亡。TLR4激活还诱导肿瘤坏死因子相关凋亡诱导配体（TRAIL）及其受体DR4和DR5上调，TRAIL抗体中和可改善TLR4诱导的凋亡，提示TRAIL及其受体DR4和DR5参与LPS诱导的细胞死亡。同时，LPS处理下调了死亡受体诱导的细胞死亡抑制因子——FLICE抑制蛋白（FLIP）的表达。此外，TLR4激活下调抗凋亡蛋白bcl-2，并上调促凋亡蛋白Noxa和Puma，提示线粒体凋亡途径也参与LPS诱导的细胞死亡。此外，我们发现TAP63α可能参与内源性和外源性凋亡途径的激活。用LPS处理THP-1细胞可诱导TAP63α从细胞质转位至细胞核。综上所述，我们的研究提示死亡受体和线粒体均参与TLR4诱导的细胞死亡，且TAP63α可能是预防LPS诱导的细胞死亡的一个靶点。
