NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1.

TitleNF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1.
Publication TypeJournal Article
Year of Publication1994
AuthorsKlampfer L, Lee TH, Hsu W, Vilcek J, Chen-Kiang S
JournalMol Cell Biol
Date Published1994 Oct
KeywordsBase Sequence, CCAAT-Enhancer-Binding Proteins, Cell Adhesion Molecules, Cells, Cultured, Cytokines, DNA Mutational Analysis, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Humans, Interleukin-1, Molecular Sequence Data, Nuclear Proteins, Promoter Regions, Genetic, Repressor Proteins, Sequence Deletion, Signal Transduction, Transcription Factor AP-1, Transcription Factors, Transcription, Genetic, Tumor Necrosis Factor-alpha

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.

Alternate JournalMol Cell Biol
PubMed ID7935377
PubMed Central IDPMC359186
Grant ListR35CA49731 / CA / NCI NIH HHS / United States
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Selina Chen-Kiang, Ph.D.

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