Klampfer L, Lee T H, Hsu W, Vilcek J, Chen-Kiang S
Department of Microbiology, New York University Medical Center, New York 10016.
Mol Cell Biol. 1994 Oct;14(10):6561-9. doi: 10.1128/mcb.14.10.6561-6569.1994.
Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.
肿瘤坏死因子α（TNF-α）和白细胞介素-1（IL-1）通过一个包含AP-1和NF-IL6位点的启动子区域（-165至-58）激活正常人成纤维细胞中TSG-6基因的转录。我们通过缺失分析和置换诱变表明，这两个位点对于TNF-α的激活都是必需的。IL-1的激活需要NF-IL6位点，并且AP-1位点可增强这种激活作用。这些结果表明，NF-IL6和AP-1家族转录因子在功能上协同作用以介导TNF-α和IL-1信号。与此可能性一致地，IL-1和TNF-α显著增加Fos和Jun与AP-1位点的结合，并且NF-IL6激活天然TSG-6启动子。NF-IL6的激活需要完整的NF-IL6位点，并且受从不同读框AUG翻译而来的激活剂与抑制剂NF-IL6同工型比例的调节。然而，抑制剂同工型也可以结合到AP-1位点并抑制AP-1位点介导的转录。抑制剂同工型拮抗IL-1和TNF-α对天然TSG-6启动子的激活这一发现表明，NF-IL6在这些细胞因子反应中具有生理作用。因此，功能不同的NF-IL6同工型与Fos和Jun协同作用，通过TNF-α和IL-1对天然TSG-6启动子进行正向和负向调节。
