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，广泛应用于临床治疗自身免疫性疾病，如多发性硬化症；IFNa/p发挥其有益作用的机制仍然难以捉摸。STAT转录因子已被确定为IFNo/p诱导的信号级联的重要组成部分。STAT1和STAT2在IFNa/p的作用下被酪氨酸磷酸化，这一过程是由酪氨酸激酶Jak1和Tyk2介导的。随后，这些STAT蛋白转运到细胞核，在那里它们与不同的增强子元件相互作用以诱导转录。STAT1已被证明是几乎所有IFNo/p激活的转录反应的重要组成部分。尽管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被很好地理解，但对于控制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细胞强大的丝裂原，它的产生是T细胞活化的标志。因此，重点放在阐明T细胞受体参与导致IL-2基因转录诱导的机制上。相比之下，通过干预信号事件导致抑制IL-2产生的过程知之甚少。我们最近发现IFNp能有效抑制活化的人和小鼠T细胞中IL-2的产生。引人注目的是，这种发生在转录水平上的抑制甚至发生在stat1缺失的T细胞中。本文提出的研究旨在定义介导IFNp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IFNp调节（转录）因子。由于IL-2的产生是启动适应性免疫反应的重要步骤，我们发现IL-2的产生受到IFNflis的负调控，这可能为T细胞活化的控制过程提供新的见解。拟议的研究还将促进对I型干扰素有效治疗自身免疫性疾病的分子机制的更好理解。

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.