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*
- From the Section of Rheumatology, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607
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 COL1A2transcription, 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 restoredCOL1A2 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 regulateCOL1A2 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.
Footnotes
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↵* This work was supported by National Institutes of Health Grants AR42309 (to J. V.) and AR46390 (to A. K. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: Section of Rheumatology (M/C733), University of Illinois Chicago College of Medicine, 1158 Molecular Biology Research Bldg., 900 S. Ashland Ave., Chicago, IL 60607. Tel.: 312-413-9310; Fax: 312-413-9271; E-mail: jvarga@uic.edu.
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Published, JBC Papers in Press, December 29, 2000, DOI 10.1074/jbc.M004709200
- Abbreviations:
- TGF-β
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transforming growth factor-β
- CBP
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CREB-binding protein
- IFN
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interferon
- GAS
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γ-activated sites
- bp
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base pair(s)
- CAT
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chloramphenicol acetyltransferase
- SBE
-
Smad-binding element
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- Received May 31, 2000.
- Revision received December 28, 2000.
- The American Society for Biochemistry and Molecular Biology, Inc.
