Interferon actions and autoimmune disorders

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DESCRIPTION (provided by applicant): Type I interferons (IFNa/p) represent a group of cytokines that finds widespread clinical application in the treatment of autoimmune disorders such as multiple sclerosis, however; the mechanisms by which IFNa/p exert their beneficial effects remain elusive. The STAT transcription factors have been identified as an important part of the IFNo/p induced signaling cascade. STAT1 and STAT2 become tyrosine phosphorylated in response to IFNa/p, an event that is mediated by the tyrosine kinases Jak1 and Tyk2. Subsequently, these STAT proteins translocate to the nucleus where they interact with distinct enhancer elements to induce transcription. STAT1 has been shown to be an essential component of virtually all IFNo/p-activated transcriptional responses. Although the role of STAT proteins (and other transcription factors) in the transcriptional activation by interferon receptor signaling is reasonably well understood, much less is known about the events that govern IFN-induced transcriptional suppression. Interleukin 2 (IL-2) is powerful mitogen for T cells, and its production is a hallmark of T cell activation. As such, much emphasis has been placed on the elucidation of the mechanism by which T cell receptor engagement leads to the transcriptional induction of the IL-2 gene. In comparison, much less is known about the processes that lead to the suppression of such IL-2 production by intervening signaling events. We recently discovered that IFNp potently inhibits IL-2 production of activated human and murine T cells. Strikingly, this suppression, which occurs at the transcriptional level, takes place even in STAT1-deficient T cells. The studies proposed here are aimed to define the IL-2 promoter elements that mediate the transcriptional suppression by IFNp, and to identify and characterize the IFNp-regulated (transcription) factor(s) that facilitate this inhibition. Since IL-2 production is a vital step in the initiation of adaptive immune responses, our finding that IL-2 production is subject to negative regulation by IFNflis likely to provide new insights into the processes governing T cells activation. The proposed studies will also promote a better understanding of the molecular mechanisms by which type I interferons are effective in the treatment of autoimmune disorders.