Transforming Growth Factor /Smad3 Signaling Regulates IRF-7 Function and Transcriptional Activation of the Beta Interferon Promoter

The rapid induction of alpha interferon (IFN) and IFNexpression plays a critical role in the innate immune response against viral infection. We studied the effects of transforming growth factor (TGF) and its intracellular effectors, the Smads, on the function of IRF-7, an essential transcription factor for IFNand induction. IRF-7 interacted with Smads, and IRF-7, but not IRF-3, cooperated with Smad3 to activate IFNtranscription. This transcriptional cooperation occurred at the IRF-binding sequences in the IFNpromoter, and dominant-negative interference with TGFreceptor signaling and Smad3 function decreased IRF-7mediated transcription. Furthermore, elimination of Smad3 expression in Smad3 / fibroblasts delayed and decreased double-stranded RNA-induced expression of endogenous IFN, whereas restoration of Smad3 expression enhanced IFNinduction. 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 TGFsignaling. Our studies underscore a role of TGF/Smad3 signaling in IRF-7-mediated induction of IFNexpression.