title: NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1.
abstract: 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.
authors.affiliation: Department of Microbiology, New York University Medical Center, New York 10016.
authors.forename: L
authors.initials: L
authors.lastname: Klampfer
authors.forename: T H
authors.initials: TH
authors.lastname: Lee
authors.forename: W
authors.initials: W
authors.lastname: Hsu
authors.forename: J
authors.initials: J
authors.lastname: Vilcek
authors.forename: S
authors.initials: S
authors.lastname: Chen-Kiang
mesh_terms: D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D015815:Cell Adhesion Molecules; D016207:Cytokines; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D009687:Nuclear Proteins; D012097:Repressor Proteins; C072273:TNFAIP6 protein, human; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha