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

Lidija Klampfer, Tae Ho Lee, Wei Hsu, Jan Vilček, Selina Chen-Kiang

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Tumor necrosis factor alpha (TNF-α) 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-α. 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- α and IL-1 signals. Consistent with this possibility, IL-1 and TNF-α 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-α 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-α and IL-1.

Original languageEnglish
Pages (from-to)6561-6569
Number of pages9
JournalMolecular and cellular biology
Volume14
Issue number10
DOIs
Publication statusPublished - 1994 Oct

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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