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

Interleukin-12 (IL-12), IL-23 and interferon-gamma (IFN-gamma) are pivotal cytokines acting in concert with tumor necrosis factor (TNF) and IL-1 beta to shape type I immune responses against bacterial pathogens. Recently, several groups reported that type I immunity can be inhibited by IFN-alpha/beta. Here we show the extent of the inhibitory effects of IFN-alpha and IFN-beta on the responsiveness of human monocytes to Toll like receptor-ligands and IFN-gamma. Both IFN-alpha and IFN-beta strongly reduced the production of IL-12p40, IL-1 beta and TNF and the IFN-gamma induced CD54 and CD64 expression. High IFN-gamma concentrations could not counterbalance the inhibitions and IFN-alpha still inhibited monocytes 24 h after stimulation in vitro as well as in vivo in patients undergoing IFN-alpha treatment. Next, we explored the mechanism of inhibition. We confirm that IFN-alpha/beta interferes with the IFN-gamma R1 expression, by studying the kinetics of IFN-gamma R1 downregulation. However, IFN-gamma R1 downregulation occurred only after two hours of IFN-alpha/beta stimulation and was transient, which cannot explain the IFN-gamma unresponsiveness observed directly and late after IFN-alpha/beta stimulation. Additional experiments indeed indicate that other mechanisms are involved. IFN-alpha may interfere with IFN-gamma-elicited phosphorylation of signal transducer and activator of transcription 1 (STAT1). IFN-alpha, may also activate methyltransferases which in turn reduce, at least partly, the TNF and IL-1 beta production and CD54 expression. IFN-alpha also induces the protein inhibitor of activated STAT1 (PIAS1). In conclusion, IFN-alpha and IFN-beta strongly inhibit the IFN-gamma responsiveness and the production of type I cytokines of monocytes, probably via various mechanisms. Our findings indicate that IFN-alpha/beta play a significant role in the immunopathogenesis of bacterial infections, for example Mycobacterium tuberculosis infection. (c) 2012 Elsevier Ltd. All rights reserved.