Interferon actions and autoimmune disorders

描述（由申请人提供）：I型干扰素（IFNa/p）代表一组细胞因子，其在治疗自身免疫性疾病如多发性硬化症中具有广泛的临床应用;然而，IFNa/p发挥其有益作用的机制仍然难以捉摸。STAT转录因子已被鉴定为IFNo/β诱导的信号级联的重要部分。STAT 1和STAT 2响应于IFNa/p而变得酪氨酸磷酸化，这是由酪氨酸激酶Jak 1和Tyk 2介导的事件。随后，这些STAT蛋白易位到细胞核，在那里它们与不同的增强子元件相互作用以诱导转录。STAT 1已被证明是几乎所有IFN 0/β激活的转录反应的重要组成部分。虽然STAT蛋白（和其他转录因子）在干扰素受体信号传导的转录激活中的作用已经相当清楚，但关于IFN诱导的转录抑制的事件知之甚少。白细胞介素2（IL-2）是T细胞的强有力的促分裂原，其产生是T细胞活化的标志。因此，重点放在阐明T细胞受体结合导致IL-2基因转录诱导的机制上。相比之下，对通过干预信号事件导致抑制这种IL-2产生的过程知之甚少。我们最近发现IFN β有效地抑制活化的人和鼠T细胞的IL-2产生。引人注目的是，这种发生在转录水平上的抑制甚至发生在STAT 1缺陷的T细胞中。本文提出的研究旨在定义介导IFN β转录抑制的IL-2启动子元件，并鉴定和表征促进这种抑制的IFN β调节（转录）因子。由于IL-2的产生是启动适应性免疫应答的重要步骤，因此我们发现IL-2的产生受到IFN β的负调控，这可能为T细胞活化的过程提供新的见解。拟议的研究也将促进更好地了解I型干扰素有效治疗自身免疫性疾病的分子机制。

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.