Furthermore, in addition to the noncanonical pathway, type I IFNs activate MAPK and PI3K

signaling leading to activation of the transcription factors AP-1 and CREB and to the activation of the mTOR complex with profound impact on, for example, T-cell biology [100]. Importantly, the activation of all the factors mentioned above is context dependent and can be both pro- or anti-inflammatory and pro- or anti-apoptotic. As STAT3 is known to be critical for the generation of Th17 cells [101, 102], it is therefore possible that Th17-cell differentiation NSC 683864 molecular weight can be supported by noncanonical IFNAR-mediated STAT3 activation. In addition, it is also possible that type I IFN may support IL-17 production by participating in the induction of the production of cytokines, such as IL-6, that are important for Th17-cell differentiation [103]. Type I IFN (IFN-β) treatment has been used successfully in patients with MS for many years. However, the mechanisms underlying the therapeutic efficacy of type I IFN are still not

well understood. Studies showing that IFN-β limits Th17-cell development by inducing IL-27 and downregulating RORc, IL-17A, and IL-23R in T cells [89, 104] prompted the idea that type I IFN was beneficial in the context of MS by antagonizing deleterious Th17-cell responses. However, 10–50% of patients with MS do not respond to IFN-β therapy, and recent studies in animal models suggest that the outcome Selleckchem Ruxolitinib of IFN-β treatment may depend on the Th1 versus Th17 phenotype of the disease. IFN-β was found to be effective in reducing EAE symptoms induced by transfer of Th1 cells whereas it actually aggravated

the disease induced by Th17 cells [105]. These findings were mirrored by the situation in humans, as IFN-β nonresponders had higher serum levels of IL-17F than responders [105]. It may therefore be that the therapeutic Rho efficacy of type I IFN in MS does not rely on a direct inhibition of Th17 responses, but on a more complex context-dependent action, for example in the regulation of Th1- and Th17-driven inflammation. Alternatively, some of the positive effects of IFN-β therapy in MS may be due to the effect of IFN-β on the blood–brain barrier [106]. The relative efficacy of IFN-β treatment for Th17-driven diseases can also be questioned based on the results in ulcerative colitis patients, as IFN-β therapy nonresponders have been shown to have higher production of IL-17 by lamina propria T cells before treatment than responders [107]. Taken together, all these data suggest that type I IFN may not directly antagonize Th17 responses and that, under some conditions as may be the case in SLE, both arms of the immune system, that is type I IFN and Th17 responses, may actually cooperate to promote disease. Type I IFN expression is mediated by three members of the IRF family of transcription factors, IRF3, IRF5, and IRF7.