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

Among the extracellular signals that modulate the synthesis of collagen, tr ansforming growth factor-beta (TGF-beta) and interferon-gamma (IFN-gamma) a re preeminent. These two cytokines exert antagonistic effects on fibroblast s, and play important roles in the physiologic regulation of extracellular matrix turnover. We have shown previously that in normal skin fibroblasts, TGF-beta positively regulates alpha2(I) procollagen gene (COL1A2) promoter activity through the cellular Smad signal transduction pathway. In contrast , IFN-gamma activates Stat1 alpha, down-regulates COL1A2 transcription, and abrogates its stimulation induced by TGF-beta, The level of integration of the two pathways mediating antagonistic collagen regulation is unknown. We now report that IFN-gamma abrogates TGF-beta -stimulated COL1A2 transcript ion in fibroblasts by inhibiting Smad activities. IFN-gamma appears to indu ce competition between activated Stat1 alpha and Smad3 for interaction with limiting amounts of cellular p300/CBP, Overexpression of p300 restored COL 1A2 stimulation by TGF-beta in the presence of IFN-gamma, and potentiated I FN-beta -dependent positive transcriptional responses. In contrast to fibro blasts, in U4A cells lacking Jak1 and consequently unable to activate Stat1 alpha -mediated responses, IFN-gamma failed to repress TGF-beta -induced t ranscription. These results indicate that as essential coactivators for bot h Smad3 and Stat1 alpha, nuclear p300/CBP integrate signals that positively or negatively regulate COL1A2 transcription. The findings implicate a nove l mechanism to account for antagonistic interaction of Smad and Jak-Stat pa thways in regulation of target genes. In fibroblasts responding to cytokine s with opposing effects on collagen transcription, the relative levels of c ellular coactivators, and their interaction with regulated transcription fa ctors, may govern the net effect.