Genes induced by IFN-beta, IFN-gamma or unphosphoraylted STAT1 in human fibroblasts

A single high dose of IFNβ activates powerful cellular responses in which many antiviral, pro-apoptotic, and anti-proliferative proteins are highly expressed. Since some of these proteins are deleterious, cells down-regulate this initial response rapidly. However, the expression of many antiviral proteins that do no harm is sustained, prolonging a substantial part of the initial antiviral response for days and also providing resistance to DNA damage. While the transcription factor ISGF3 (IRF9 and tyrosine-phosphorylated STATs 1 and 2) drives the first rapid response phase, the related factor un-phosphorylated ISGF3 (U-ISGF3), formed by IFNβ-induced high levels of IRF9 and STATs 1 and 2 without tyrosine phosphorylation, drives the second prolonged response. The U-ISGF3-induced antiviral genes that show prolonged expression are driven by distinct interferon stimulated response elements (ISREs). Continuous exposure of cells to a low level of IFNβ, often seen in cancers, leads to steady-state increased expression of only the U-ISGF3-dependent proteins, with no sustained increase of other IFNβ-induced proteins, and to constitutive resistance to DNA damage. We classified genes into U-ISGF3-induced genes and classical ISGF3-induced genes using microarray data. We identified 150 genes that are up-regulated by IFNβ after 6 h. Among these IFNβ-induced genes, only 29 (20%) were induced by the up-regulation of Y701F-STAT1, indicating that these are induced by U-ISGF3. Among the remaining 121 IFNβ-induced genes (150 minus 29), 73 are induced by IFNγ as well as IFNβ, and 48 are induced only by IFNβ.