Editorial IFNbeta

A Tail of Two STATS In 1993 the US FDA approved the first disease modifying drug - Interferon-β (IFN-β, Betaseron®) for the treatment of relapsing remitting multiple sclerosis (RRMS), a debilitating disease of the central nervous system (CNS) affecting young adults. MS is a chronic demyelinating autoimmune disease of unknown etiology and heterogeneous clinical symptoms and course characterized by CNS inflammation, resulting in axonal damage and subsequently neurological disability. IFN-β markedly reduces lesion formation, rate of relapses and brain atrophy. Despite the long-standing use of IFN-β in RRMS the precise mechanisms underlying the effects of IFN-β remain poorly understood. Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of MS have implicated myeloid cell subsets as important targets for mediating the immunosuppressive actions of IFN-β in CNS autoimmunity. Conditional deletion of the type I interferon receptor (IFNAR) in myeloid cells but not in T cells or neuroectodermal CNS cells exacerbates EAE and suggests that the protective effects of IFN-β are mediated by myeloid cells. IFN-β engagement of IFNAR on both peripheral and CNS myeloid cells resulted in downregulation of the proinflammatory Th1/Th17 environment and ameliorated EAE disease severity and course. What myeloid cells are specifically affected by IFN-β remains to be determined, although both dendritic cells (DC) and macrophages are recognized as key regulators of CNS autoimmunity. DCs play a pivotal role in the priming of naïve T cells in the periphery during the initial phase of CNS autoimmunity. The nature and effectiveness of T cell priming depends on the DC phenotype with respect to the activation and maturation status. Depending upon the stimulus received, DCs may promote the development of tolerogenic as well as proinflammatory T cell responses. The stimulus may constitute pathogen components or endogenous danger signals, such as type I IFNs which lead to DC activation and maturation. Recognition of pathogen components leads to the upregulation of MHCII and costimulatory molecules such as CD80 and CD86 on DCs and secretion of proinflammatory cytokines, IL-1β, IL-12 and IL-23 leading to the differentiation of CD4+ T cells into Th1 and Th17 cells. DCs have been shown to promote neuroinflammation in EAE primarily by their effect on the differentiation and expansion of Th1 and Th17 cells. Moreover, DCs produce IFN-β and respond to IFN-β after signaling through IFNAR. The major signaling pathway downstream of IFNAR involves ISGF3 heterodimers comprised of STAT1, STAT2 and IRF9 which translocate to the nucleus, bind to ISRE sequences and induce the expression of IRF genes. IFN-β has also been shown to activate the PI3K/Akt pathway resulting in GSK3 phosphorylation. In this issue, Yen et al ( ) investigate the effects of IFN-β on cDC expression of cytokines involved in the regulation of Th1/Th17 differentiation and expansion and the role of signaling pathways involved in mediating the effects of IFN-β on cytokine expression. They confirm that IFN-β inhibits the Th1/Th17 response that leads to CNS autoimmunity by suppressing the cytokines that promote these T helper phenotypes. They further demonstrate that IFN-β affected cytokine expression in TLR-stimulated DC in a similar manner in vitro, inhibiting IL-12

and IL-23 and stimulating IL-10 at both mRNA and protein level, by signaling through the IFNAR. They showed that IFN-β inhibition of the p40 and p35, the IL-12 subunits was mediated through STAT1/STAT2, but not IRF1 or IRF7. The inhibitory effect of IFN-β on IL-12 appears to be mediated through activation of the PI3K signaling pathway. IFN-β inhibition of IL-23 expression was STAT1 dependent and partially by STAT2 and IRF1 or IRF7 was not responsible for the inhibitory effect of IFN-β on IL-23. Interestingly, the inhibitory effect of IFN-β on IL-23 was not mediated by IL-27 as has been reported both in mice and human studies. …. The molecular mechanisms involved in the inhibition of IL-23 expression by IFN-β remain to be elucidated. IFN-β inhibition of IL-23 is of therapeutic significance as decreases in IL-23 have been reported in RRMS patients on IFN-β therapy. The authors report for the first time that STAT2 is involved in the stimulatory effect of IFN-β on IL-10 expression and that PI3K and GSK3 do not mediate the IL-10 upregulation by IFN-β. Since the discovery of the involvement of the Jak-STAT pathway in IFNAR signaling, numerous studies have elucidated the involvement of other signaling molecules regulating the Jak/STAT pathway as well as identified non-STAT pathways. The paper by Liu at al suggests yet another possible pathway and adds to the complexing by which type I IFNs of signal via IFNAR. Their data suggests that IFN-β signaling via the IFNAR can initiate three different outcomes; the first one is the activation of STAT1/STAT2 and PI3K that leads to inhibition of IL-12. The second course is the activation of STAT1 along with a partial STAT2 activation resulting in IL-23 inhibition whereas the third pathway activates only STAT2 and leads to upregulation of IL-10. IRF1 and IRF7 were not involved in any of the three pathways. This raises the question of what drives the promotion of the different pathways.

Further understanding of IFN-mediated signaling may provide clues to the development of new agents and efficient therapeutic strategies.

New potential pathways by which type 1 interferon signaling via the JAK-STAT complex occurs are described. Pictured from left to right, Christine Rohowsky-Kochan and Patricia FitzgeraldBocarsly