USP18 establishes the transcriptional and anti-proliferative interferon alpha/beta differential

Introduction Type I interferons (IFNs) are pathogen-induced immunoregulatory cytokines that exert antiviral and anti-proliferative activities through binding to a common cell surface receptor. Among the 17 human IFN subtypes, IFN β binds the IFNAR1/IFNAR2 receptor chains with particularly high affinity and is especially potent in select bioactivities (e.g. anti-proliferative and pro-apoptotic) when compared to IFN α2. However, no molecular basis has been ascribed to this differential action, since the two ligands are equipotent in immediate early signaling events. Methods Using standard immunoassays we monitored Stat phosphorylation and interferon stimulated gene (ISG) protein accumulation in response to prolonged treatment with IFN α2 or IFN β, while monitoring ISG mRNA levels by qPCR and proliferation by crystal violet staining. RNA interference was used to assess the role of USP18 in establishing differential Stat signaling, ISG mRNA and protein production, and anti-proliferative responses in response to the two type-I interferon subtypes. Results Here we report that IFN β induces Stat phosphorylation and transcriptional activation of ISGs, including two genes with pro-apoptotic functions, for a considerably longer time frame than IFN α2. We show that the diversification of α2/β responses progressively builds up at the receptor level as a result of accumulating USP18, itself an ISG, which exerts its negative feeback action by taking advantage of the weakness of IFN α2 binding to the receptor. Conclusion This represents a novel type of signaling regulation that diversifies the biological potential of IFNs α and β.