Interferon-τ (IFNτ) regulation of IFN-stimulated gene expression in cell lines lacking specific IFN-signaling components

Abstract

Interferon-τ (IFNτ) is a unique type I IFN secreted by the ruminant conceptus that acts in a paracrine manner on the endometrial epithelium to signal pregnancy recognition. In the ovine endometrium, IFNτ suppresses estrogen receptor α and oxytocin receptor gene expression, but increases or induces expression of IFN-simulated genes (ISGs), including signal transducer and activator of transcription-1 (STAT1), STAT2, ISG factor-3γ (ISGF3γ)/p48/IFN regulatory factor-9, and 2′,5′-oligoadenylate synthetase (OAS). Human fibroblast cell lines lacking specific IFN signaling components were employed to determine the roles of STAT1, STAT2, and ISGF3γ in the effects of IFNτ on ISG protein expression. Results indicated that STAT1α or STAT1β is required for IFNτ effects on STAT2, ISGF3γ, and OAS (40/46, 69/71, and 100 kDa). STAT2 is required for effects on STAT1, ISGF3γ, and all OAS forms. IS GF3γ is required for effects of IFNτ on STAT2 and 40/46- and 69/71-kDa GAS and plays a role in the effects of IFNτ on 100-kDa OAS and STAT1. Mutation of Tyr701, but not Ser727, of STAT1 abolished the effects of IFNτ on ISG expression. Mutation of the SH2 domain of STAT1 abolished the effects of IFNτ on all ISGs and reduced increases in 100-kDa OAS. These data illustrate the importance of transcription factors composed of STAT1, STAT2, and ISGF3γ in the signaling pathway mediating the effects of IFNτ on ISG expression.