Inhibition of the type I immune responses of human monocytes by IFN-α and IFN-β

Interleukin-12 (IL-12), IL-23 and interferon-γ (IFN-γ) are pivotal cytokines acting in concert with tumor necrosis factor (TNF) and IL-1β to shape type I immune responses against bacterial pathogens. Recently, several groups reported that type I immunity can be inhibited by IFN-α/β. Here we show the extent of the inhibitory effects of IFN-α and IFN-β on the responsiveness of human monocytes to Toll like receptor-ligands and IFN-γ. Both IFN-α and IFN-β strongly reduced the production of IL-12p40, IL-1β and TNF and the IFN-γ induced CD54 and CD64 expression. High IFN-γ concentrations could not counterbalance the inhibitions and IFN-α still inhibited monocytes 24 h after stimulation in vitro as well as in vivo in patients undergoing IFN-α treatment. Next, we explored the mechanism of inhibition. We confirm that IFN-α/β interferes with the IFN-γR1 expression, by studying the kinetics of IFN-γR1 downregulation. However, IFN-γR1 downregulation occurred only after two hours of IFN-α/β stimulation and was transient, which cannot explain the IFN-γ unresponsiveness observed directly and late after IFN-α/β stimulation. Additional experiments indeed indicate that other mechanisms are involved. IFN-α may interfere with IFN-γ-elicited phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-α may also activate methyltransferases which in turn reduce, at least partly, the TNF and IL-1β production and CD54 expression. IFN-α also induces the protein inhibitor of activated STAT1 (PIAS1). In conclusion, IFN-α and IFN-β strongly inhibit the IFN-γ responsiveness and the production of type I cytokines of monocytes, probably via various mechanisms. Our findings indicate that IFN-α/β play a significant role in the immunopathogenesis of bacterial infections, for example Mycobacterium tuberculosis infection.

► IFN-α and IFN-β strongly inhibit the type I immune responses of human monocytes. ► High concentrations of IFN-γ do not counterbalance the inhibition by IFN-α/β. ► The inhibitory effects of IFN-α last for at least 24 h, in vitro and in vivo. ► Downregulation of IFN-γR1 by IFN-α is not the only cause of IFN-γ unresponsiveness. ► Other putative mechanisms are competition for STAT1 and activation of PRMTs and PIAS1.