Type I IFNs differentially modulate IL-12p70 production by human dendritic cells depending on the maturation status of the cells and counteract IFN-γ-mediated signaling

Type I IFNs (IFNα/β) are approved for the treatment of a variety of diseases, including the autoimmune disease multiple sclerosis (MS). The proinflammatory cytokines IL-12 and IFN-γ have been proposed to contribute to the pathogenesis of MS. Since dendritic cells (DCs) are recognized as major producers of IL-12p70 and promote the development of IFN-γ-producing Th1 cells, we investigated the direct effect of IFNα/β on monocyte-derived DCs at different stages of development. We demonstrate that IFNα/β enhance IL-12p70 production by immature DCs but inhibit IL-12p70 production by mature DCs. Importantly, IFNα/β strongly counteracted the IL-12-enhancing effect of IFN-γ on DCs irrespective of their maturation status. Exposure of DCs to IFNα/β during maturation does not affect their maturation or cytokine profile upon CD40 ligation. The differential modulatory effect of IFNα/β on the IL-12-producing capacity of DCs and their cross-regulatory effect on IFN-γ may reduce inflammatory processes and therefore be therapeutically effective in MS.