Chawla-Sarkar M, Lindner D J, Liu Y-F, Williams B R, Sen G C, Silverman R H, Borden E C
Center for Drug Discovery and Development, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Apoptosis. 2003 Jun;8(3):237-49. doi: 10.1023/a:1023668705040.
IFNs are a family of cytokines with pleiotropic biological effects mediated by scores of responsive genes. IFNs were the first human proteins to be effective in cancer therapy and were among the first recombinant DNA products to be used clinically. Both quality and quantity of life has been improved in response to IFNs in various malignancies. Despite its beneficial effects, unraveling the mechanisms of the anti-tumor effects of IFN has proven to be a complex task. IFNs may mediate anti-tumor effects either indirectly by modulating immunomodulatory and anti-angiogenic responses or by directly affecting proliferation or cellular differentiation of tumor cells. Both direct or indirect effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). In addition to the ISGs implicated in anti-viral, anti-angiogenic, immunomodulatory and cell cycle inhibitory effects, oligonucleotide microarray studies have identified ISGs with apoptotic functions. These include TNF-alpha related apoptosis inducing ligand (TRAIL/Apo2L), Fas/FasL, XIAP associated factor-1 (XAF-1), caspase-4, caspase-8, dsRNA activated protein kinase (PKR), 2'5'A oligoadenylate synthetase (OAS), death activating protein kinases (DAP kinase), phospholipid scramblase, galectin 9, IFN regulatory factors (IRFs), promyelocytic leukemia gene (PML) and regulators of IFN induced death (RIDs). In vitro IFN-alpha, IFN-beta and IFN-gamma induced apoptosis in multiple cell lines of varied histologies. This review will emphasize possible mechanisms and the role of ISGs involved in mediating apoptotic function of IFNs.
干扰素是一类细胞因子，具有由众多应答基因介导的多效性生物学效应。干扰素是首批在癌症治疗中有效的人类蛋白质，也是首批用于临床的重组DNA产品。在各种恶性肿瘤中，干扰素治疗后患者的生活质量和数量均有所改善。尽管干扰素具有有益作用，但阐明其抗肿瘤作用机制却是一项复杂的任务。干扰素可能通过调节免疫调节和抗血管生成反应间接介导抗肿瘤作用，也可能直接影响肿瘤细胞的增殖或细胞分化。干扰素的直接或间接作用均源于一组被称为干扰素刺激基因（ISG）的基因的诱导。除了与抗病毒、抗血管生成、免疫调节和细胞周期抑制作用相关的ISG外，寡核苷酸微阵列研究还鉴定出了具有凋亡功能的ISG。这些包括肿瘤坏死因子-α相关凋亡诱导配体（TRAIL/Apo2L）、Fas/FasL、XIAP相关因子-1（XAF-1）、半胱天冬酶-4、半胱天冬酶-8、双链RNA激活蛋白激酶（PKR）、2'5'A寡腺苷酸合成酶（OAS）、死亡激活蛋白激酶（DAP激酶）、磷脂翻转酶、半乳糖凝集素9、干扰素调节因子（IRF）、早幼粒细胞白血病基因（PML）和干扰素诱导死亡调节因子（RID）。体外实验中，干扰素-α、干扰素-β和干扰素-γ可诱导多种不同组织学类型的细胞系发生凋亡。本综述将重点阐述干扰素介导凋亡功能的可能机制以及ISG的作用。
