Akira S, Kishimoto T
Institute for Molecular and Cellular Biology, Osaka University, Japan.
Immunol Rev. 1992 Jun;127:25-50. doi: 10.1111/j.1600-065x.1992.tb01407.x.
NF-IL6 was originally identified as a DNA-binding protein responsible for IL-1-stimulated IL-6 induction. Direct cloning of NF-IL6 revealed its homology with C/EBP. C/EBP is expressed in liver and adipose tissues and is supposed to regulate several hepatocyte- and adipocyte-specific genes. In contrast, NF-IL6 is suppressed in normal tissues, but is rapidly and drastically induced by LPS or inflammatory cytokines such as IL-1, TNF, and IL-6. NF-IL6 can also bind to the regulatory region of various genes including IL-8, G-CSF, IL-1 and immunoglobulin genes. Furthermore, NF-IL6 is shown to be identical to IL-6DBP, a DNA-binding protein responsible for IL-6-mediated induction in acute-phase proteins, demonstrating that NF-IL6 is responsible for the genes regulated by IL-6. These results indicate that NF-IL6 may be a pleiotropic mediator of many inducible genes involved in acute, immune, and inflammatory responses, like NFkB. In this regard, it is noteworthy that both an NF-IL6 binding site and an NFkB binding site are present in the inducible genes such as IL-6, IL-8, and several acute-phase genes. On the other hand, accumulating evidence has revealed that overproduction of IL-6 may be responsible for the pathogenesis and/or several symptoms of a variety of diseases, including autoimmune diseases, malignancies, and viral diseases. At present, the molecular mechanisms of abnormal expression of the IL-6 gene are not known. Recently it has become evident that interplays between viral proteins and cellular proteins play an important role in viral oncogenesis and infection. The fact that NF-IL6 binds to the enhancer core sequences of various viruses strongly suggests a possible relationship of virus infection and IL-6 expression. In fact some evidence (Mahe et al. 1991, Spergel et al. 1992) indicates that NF-IL6 may interact with viral gene enhancers or viral products, although there are no definite data about the involvement of NF-IL6 in viral pathogenesis. Future studies will be required to clarify whether or not the interplay between NF-IL6 and viral infection is responsible for deregulation of the IL-6 gene.
NF-IL6最初被鉴定为一种DNA结合蛋白，负责IL-1刺激的IL-6诱导。NF-IL6的直接克隆揭示了它与C/EBP的同源性。C/EBP在肝脏和脂肪组织中表达，被认为可调节几种肝细胞和脂肪细胞特异性基因。相比之下，NF-IL6在正常组织中受到抑制，但可被LPS或炎症细胞因子如IL-1、TNF和IL-6迅速且显著地诱导。NF-IL6还可与包括IL-8、G-CSF、IL-1和免疫球蛋白基因在内的多种基因的调控区域结合。此外，NF-IL6被证明与IL-6DBP相同，IL-6DBP是一种负责急性期蛋白中IL-6介导诱导的DNA结合蛋白，这表明NF-IL6负责由IL-6调控的基因。这些结果表明，NF-IL6可能是许多参与急性、免疫和炎症反应的诱导基因的多效性介质，就像NFkB一样。在这方面，值得注意的是，在诸如IL-6、IL-8和几种急性期基因等诱导基因中同时存在NF-IL6结合位点和NFkB结合位点。另一方面，越来越多的证据表明，IL-6的过度产生可能与包括自身免疫性疾病、恶性肿瘤和病毒性疾病在内的多种疾病的发病机制和/或几种症状有关。目前，IL-6基因异常表达的分子机制尚不清楚。最近已经很明显，病毒蛋白和细胞蛋白之间的相互作用在病毒致癌作用和感染中起重要作用。NF-IL6与各种病毒的增强子核心序列结合这一事实强烈暗示了病毒感染与IL-6表达之间可能存在的关系。事实上，一些证据（Mahe等人，1991年；Spergel等人，1992年）表明NF-IL6可能与病毒基因增强子或病毒产物相互作用，尽管关于NF-IL6参与病毒发病机制尚无确切数据。未来的研究将需要阐明NF-IL6与病毒感染之间的相互作用是否导致IL-6基因失调。
