ACTIVATION OF INTERLEUKIN-6 GENE-EXPRESSION THROUGH THE NF-KAPPA-B TRANSCRIPTION FACTOR
ACTIVATION OF INTERLEUKIN-6 GENE-EXPRESSION THROUGH THE NF-KAPPA-B TRANSCRIPTION FACTOR
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DOI：
10.1128/mcb.10.5.2327
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发表时间：
1990-05-01
影响因子：
5.3
通讯作者：
BALTIMORE, D
中科院分区：
文献类型：
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作者：
LIBERMANN, TA;BALTIMORE, D
白细胞介素-6（IL-6）基因的启动子区具有推定的NF-κ B结合位点。我们发现含有该位点的IL-6启动子片段特异性结合高度纯化的NF-κ B蛋白和佛波酯诱导的Jurkat细胞核提取物中的NF-κ B蛋白。NF-κ B位点的突变消除了与纯化的NF-κ B和核提取蛋白的复合物形成。含有IL-6启动子的氯霉素乙酰转移酶（CAT）质粒的瞬时表达揭示了在刺激前U-937单核细胞和HeLa细胞中启动子的活性非常小。然而，通过NF-κ B的诱导剂刺激U-937和HeLa细胞导致CAT活性的显著增加。NF-κ B结合位点的突变消除了U-937细胞中IL-6启动子-cat构建体被脂多糖、肿瘤坏死因子α双链RNA聚（IC）或植物血凝素以及HeLa细胞中的肿瘤坏死因子α。并且在双链RNA poly（IC）或佛波醇12-肉豆蔻酸酯13-乙酸酯刺激的HeLa细胞中显著降低但不能完全消除诱导性。这些结果表明，NF-κ B是U-937和HeLa细胞中通过多种IL-6诱导剂激活IL-6基因的重要介质，并且可选择的可诱导增强子元件以细胞特异性方式促进IL-6基因诱导。因为NF-κ B参与控制炎症时激活的多种基因，所以NF-κ B可能在对感染和组织损伤的炎症反应中起中心作用。
The promoter region of the interleukin-6 (IL-6) gene has a putative NF-.kappa.B-binding site. We found that a fragment of the IL-6 promoter containing the site specifically binds highly purified NF-.kappa.B protein and the NF-.kappa.B protein in nuclear extracts of phorbol ester-induced Jurkat cells. Mutations of the NF-.kappa.B site abolished complex formation with both purified NF-.kappa.B and the nuclear extract protein. Transient expression of chloramphenicol acetyltransferase (CAT) plasmids containing the IL-6 promoter revealed very little activity of the promoter in U-937 monocytic cells and in HeLa cells before stimulation. However, stimulation of U-937 and HeLa cells by inducers of NF-.kappa.B led to a dramatic increase in CAT activity. Mutations in the NF-.kappa.B-binding site abolished inducibility of IL-6 promoter-cat constructs in U-937 cells by lipopolysaccharide, tumor necrosis factor .alpha., the double-stranded RNA poly(IC), or phytohemagglutinin and in HeLa cells by tumor necrosis factor .alpha. and drastically reduced but did not completely eliminate inducibility in HeLa cells stimulated by double-stranded RNA poly(IC) or phorbol 12-myristate 13-acetate. These results suggest that NF-.kappa.B is an important mediator for activation of the IL-6 gene by a variety of IL-6 inducers in both U-937 and HeLa cells and that alternative inducible enhancer elements contribute in a cell-specific manner to IL-6 gene induction. Because NF-.kappa.B is involved in the control of a variety of genes activated upon inflammation, NF-.kappa.B may play a central role in the inflammatory response to infection and tissue injury.