Editorial: IFN-β immunomodulation: a tail of two STATS

In 1993, the U.S. Food and Drug Administration approved the first disease-modifying drug—IFN-b (Betaseron)—for the treatment of RRMS, a debilitating disease of the 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, neurologic disability. IFN-b markedly reduces lesion formation, rate of relapses, and brain atrophy [1]. Despite the longstanding use of IFN-b in RRMS, the precise mechanisms underlying the effects of IFN-b remain poorly understood. Studies in EAE, the animal model of MS, have implicated myeloid cell subsets as important targets for mediating the immunosuppressive actions of IFN-b in CNS autoimmunity. Conditional deletion of the IFNAR in myeloid cells but not in T cells or neuroectodermal CNS cells exacerbates EAE and suggests that the protective effects of IFN-b (Fig. 1) are mediated by myeloid cells [2]. IFN-b engagement of IFNAR on peripheral and CNS myeloid cells results in downregulation of the proinflammatory Th1/ Th17 environment and amelioration of EAE disease severity and course. What myeloid cells are specifically affected by IFN-b remain to be determined, although both DCs and macrophages are recognized as key regulators of CNS autoimmunity. DCs play a pivotal role in the priming of naive T cells in the periphery during the initial phase of CNS autoimmunity. The nature and effectiveness of T cell priming depend on the DC phenotype, with respect to the activation and maturation status. Depending on 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 MHC class II and costimulatory molecules, such as CD80 and CD86, on DCs and secretion of proinflammatory cytokines, IL-1b, 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 [3]. Moreover, DCs produce IFN-b and respond to IFN-b after signaling through IFNAR. Type I IFNs bind to the IFNAR complex, consisting of 2 transmembrane chains (IFNAR-1 and IFNAR-2), resulting in the activation of 2 receptor-associated tyrosine kinases, JAK1 and TYK2 [4]. Activation of JAK1 and TYK2 leads to the phosphorylation of STAT1 and STAT2, binding to IRF-9, and the formation of the ISGF3 complex that translocates to the nucleus and binds ISREs that initiate transcription of IFN-stimulated genes. In addition, to the canonical pathway, type I IFNs can induce other STAT complexes, such as STAT3 or STAT5 homodimers, STAT1-STAT3, or STAT5-Crk-like heterodimers. Type I IFNs also activate the PI3K/Akt signaling pathway, resulting in GSK3 phosphorylation [4]. In this issue of JLB, Yen et al. [5] investigate the effects of IFN-b on DC 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-b on cytokine expression. They confirm that IFN-b inhibits the Th1/ Th17 response that leads to CNS autoimmunity by suppressing the cytokines that promote these Th phenotypes. They demonstrate further that IFN-b affected cytokine expression in TLR-stimulated DCs in a similar manner in vitro, inhibiting IL-12 and IL-23 and stimulating IL-10 at mRNA and protein levels, by signaling through IFNAR. Interestingly, the inhibitory effect of IFN-b on IL-12 was mediated through a signaling cascade involving STAT1, STAT2, and PI3K activation and GSK3 inactivation. A connection between STAT1/STAT2 and PI3K/ GSK3 has not been described previously, and the intermediary substrates involved are not known. Yen et al. [5] demonstrate that IFN-b inhibition of IL-23 expression was STAT1 dependent and did not involve IRF-1, IRF-7, or IL-27. The molecular mechanisms involved in the inhibition of IL-23 expression by IFN-b remain to be elucidated. The authors report for the first time that STAT2 is involved in the