Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma

Type I (alpha, beta) and type II (gamma) interferons (IFNs) can restrict the growth of many cell types, INF-stimulated gene transcription, a key early event in IFN response, acts through the Janus, kinase-signal transducers and activators of transcription pathway, in which both IFN-alpha and IFN-gamma activate the transcription factor Stat1, A cell line lacking Stat1 (U3A) was not growth-arrested by IFN-alpha or IFN-gamma, and experiments were carried out with U3A cells permanently expressing normal or various mutant forms of Stat1 protein, Only cells in which complete Stat1 activity was available (Stat1 alpha) were growth-inhibited by IFN gamma, A mutant that supports 20-30% normal transcription did not cause growth restraint, In contrast, IFN-alpha growth restraint was imposed by cells producing Stat1 beta, which lacks transcriptional activation potential. This parallels earlier results showing the truncated Stat1 can function in IFN-alpha gene activation, In addition to experiments on long-term cultured cells, we also found that wild-type primary mouse embryonic fibroblasts were inhibited by IFNs, but fibroblasts from Stat1-deficient mouse embryos were not inhibited by IFNs.