Antagonistic regulation of type I collagen gene expression by interferon-γ and transforming growth factor-β: Integration at the level of p300/CBP transcriptional coactivators

Asish K. Ghosh, Weihua Yuan, Yasuji Mori, Shu Jen Chen, John Varga*

*Corresponding author for this work

Research output: Contribution to journalArticle

208 Scopus citations

Abstract

Among the extracellular signals that modulate the synthesis of collagen, transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ) are preeminent. These two cytokines exert antagonistic effects on fibroblasts, and play important roles in the physiologic regulation of extracellular matrix turnover. We have shown previously that in normal skin fibroblasts, TGF-β positively regulates α2(I) procollagen gene (COL1A2) promoter activity through the cellular Smad signal transduction pathway. In contrast, IFN-γ activates Stat1α, down-regulates COL1A2 transcription, and abrogates its stimulation induced by TGF-β. The level of integration of the two pathways mediating antagonistic collagen regulation is unknown. We now report that IFN-γ abrogates TGF-β-stimulated COL1A2 transcription in fibroblasts by inhibiting Smad activities. IFN-γ appears to induce competition between activated Stat1α and Smad3 for interaction with limiting amounts of cellular p300/CBP. Overexpression of p300 restored COL1A2 stimulation by TGF-β in the presence of IFN-γ, and potentiated IFN-γ-dependent positive transcriptional responses. In contrast to fibroblasts, in U4A cells lacking Jak1 and consequently unable to activate Stat1α-mediated responses, IFN-γ failed to repress TGF-β-induced transcription. These results indicate that as essential coactivators for both Smad3 and Stat1α, nuclear p300/CBP integrate signals that positively or negatively regulate COL1A2 transcription. The findings implicate a novel mechanism to account for antagonistic interaction of Smad and Jak-Stat pathways in regulation of target genes. In fibroblasts responding to cytokines with opposing effects on collagen transcription, the relative levels of cellular coactivators, and their interaction with regulated transcription factors, may govern the net effect.

Original languageEnglish (US)
Pages (from-to)11041-11048
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number14
DOIs
StatePublished - Apr 6 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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