Naujokat C, Sezer O, Possinger K
Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität Berlin, Schumannstrabetae 20/21, Berlin, 10098, Germany.
Biochem Biophys Res Commun. 1999 Nov 2;264(3):813-9. doi: 10.1006/bbrc.1999.1500.
Tumor cells develop diverse mechanisms to escape from immune surveillance, including expression of Fas ligand (FasL), a 40-kDa type II transmembrane protein that mediates apoptosis by binding to its cognate receptor Fas (APO-1/CD95). Upon activation, T lymphocytes and natural killer (NK) cells express Fas and thus become sensitive to FasL-mediated apoptosis. Here we show that tumor necrosis factor-alpha (TNF-alpha) in addition to interferon-gamma (IFN-gamma) induces cell surface expression of functional FasL in human HT29 colon and MCF7 breast adenocarcinoma cells that constitutively lack cell surface expression of FasL. These cells, expressing FasL, are capable of inducing apoptosis in Fas-positive Jurkat T cells mediated by plasma membrane-bound FasL and soluble forms of FasL. By contrast, mutational deletion of Fas cell surface expression as well as inhibition of caspase family proteases involved in Fas signaling and monoclonal antibodies neutralizing FasL protect Jurkat T cells from apoptosis caused by the FasL-expressing HT29 or MCF7 cells. These results demonstrate that TNF-alpha and IFN-gamma induce expression of functional FasL in adenocarcinoma cells which thereby can kill T lymphocytes by the FasL/Fas pathway.
肿瘤细胞会形成多种机制来逃避免疫监视，包括表达Fas配体（FasL），一种40 kDa的II型跨膜蛋白，它通过与其同源受体Fas（APO-1/CD95）结合来介导细胞凋亡。激活后，T淋巴细胞和自然杀伤（NK）细胞会表达Fas，从而对FasL介导的细胞凋亡敏感。在此我们表明，除了干扰素-γ（IFN-γ）外，肿瘤坏死因子-α（TNF-α）可诱导人HT29结肠癌细胞和MCF7乳腺腺癌细胞表面功能性FasL的表达，这些细胞原本缺乏FasL的细胞表面表达。这些表达FasL的细胞能够通过质膜结合的FasL和可溶性FasL形式诱导Fas阳性Jurkat T细胞凋亡。相比之下，Fas细胞表面表达的突变缺失以及对Fas信号通路中涉及的半胱天冬酶家族蛋白酶的抑制，以及中和FasL的单克隆抗体，可保护Jurkat T细胞免受表达FasL的HT29或MCF7细胞引起的凋亡。这些结果表明，TNF-α和IFN-γ可诱导腺癌细胞中功能性FasL的表达，从而通过FasL/Fas途径杀死T淋巴细胞。
