Transforming growth factor beta/Smad3 signaling regulates IRF-7 function and transcriptional activation of the beta interferon promoter.

Department of Growth and Development, Program in Cell Biology, University of California at San Francisco, San Francisco, California 94143, USA.
The rapid induction of alpha interferon (IFN-alpha) and IFN-beta expression plays a critical role in the innate immune response against viral infection. We studied the effects of transforming growth factor beta (TGF-beta) and its intracellular effectors, the Smads, on the function of IRF-7, an essential transcription factor for IFN-alpha and -beta induction. IRF-7 interacted with Smads, and IRF-7, but not IRF-3, cooperated with Smad3 to activate IFN-beta transcription. This transcriptional cooperation occurred at the IRF-binding sequences in the IFN-beta promoter, and dominant-negative interference with TGF-beta receptor signaling and Smad3 function decreased IRF-7-mediated transcription. Furthermore, elimination of Smad3 expression in Smad3(-/-) fibroblasts delayed and decreased double-stranded RNA-induced expression of endogenous IFN-beta, whereas restoration of Smad3 expression enhanced IFN-beta induction. The IRF-7-Smad3 cooperativity resulted from the regulation of the transactivation activity of IRF-7 by Smad3, and dominant-negative interference with Smad3 function decreased IRF-7 activity. Consistent with the regulation by Smad3, the transcriptional activity of IRF-7 depended on and was regulated by TGF-beta signaling. Our studies underscore a role of TGF-beta/Smad3 signaling in IRF-7-mediated induction of IFN-beta expression.
Mesh Terms:
Animals, Binding Sites, DNA-Binding Proteins, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Interferon-beta, Mice, Promoter Regions, Genetic, Signal Transduction, Smad2 Protein, Smad3 Protein, Trans-Activators, Transcription Factors, Transcription, Genetic, Transforming Growth Factor beta
Mol. Cell. Biol. Feb. 01, 2004; 24(3);1411-25 [PUBMED:14729983]
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