SIGNALING IN CELLS CHRONICALLY EXPOSED TO INTERFERON BETA (NMSS)

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 摘要： 在过去的十年中，已经获得了丰富的知识，关于干扰素和其他细胞因子通过Jak/Stat途径激活或下调立即早期基因的机制。然而，很少有信息是可利用的干扰素激活的基因表达的nanve细胞相比，细胞已脱敏，随后重新敏化这些细胞因子的作用，从而模仿在临床环境中重复干扰素管理。在nanve细胞中，ISG 54基因通过IFN？刺激ISGF 3的形成，ISGF 3是一种异源三聚体DNA结合复合物，由p48（IRF 9）和酪氨酸磷酸化的Stat 1和Stat 2组成，可结合干扰素刺激反应元件（ISRE）。与此相反，在以前的脱敏细胞，IFN？弱刺激缺乏酪氨酸磷酸化Stat 1的ISGF 3样复合物的组装，即使ISG 54 mRNA诱导与nanve细胞中相同。Stat 1酪氨酸磷酸化和DNA结合的缺乏是由于蛋白酪氨酸磷酸酶Tc-PTP的活性增加。虽然IFN？在先前脱敏的细胞中，ISGF 3的刺激形成减少，LPS诱导ISG 54表达的能力，推测是通过TLR 4/IRF 3依赖的信号通路，大大增强。ISRE依赖性早期应答基因的激活在先前已经对该细胞因子脱敏的细胞中是显著不同的。干扰素的修饰？这种反应影响通过与Toll受体结合的配体调节的其他转录因子调节ISG 54活化的能力。 以前脱敏细胞的反应改变可能转化为IFN？和Toll受体介导的应答。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Abstract: Over the past decade, a wealth of knowledge has been obtained concerning the mechanisms by which interferons and other cytokines activate or downregulate immediate early genes via the Jak/Stat pathway. However, little information is available on interferon-activated gene expression in nanve cells compared to cells that have been desensitized and subsequently re-sensitized to the actions of these cytokines, thereby mimicking repeated interferon administration in a clinical setting. In nanve cells, the ISG54 gene is activated via IFN?-stimulated formation of ISGF3, a heterotrimeric DNA binding complex consisting of p48 (IRF9) and tyrosine-phosphorylated Stat1 and Stat2, which binds the Interferon Stimulated Response Element (ISRE). In contrast, in previously de-sensitized cells, IFN? weakly stimulates the assembly of an ISGF3-like complex that lacks tyrosine phosphorylated Stat1, even though ISG54 mRNA induction is the same as in nanve cells. The lack of Stat1 tyrosine phosphorylation and DNA binding is due to increased activity of the protein tyrosine phosphatase Tc-PTP. Although IFN?-stimulated formation of ISGF3 is decreased in previously desensitized cells, the ability of LPS to induce ISG54 expression, presumably through an TLR4/IRF3-dependent signaling pathway, is greatly enhanced .We hypothesize that the signaling pathways that regulate type one interferon (IFN?) activation of ISRE-dependent early response genes are substantially different in cells that have been previously desensitized to this cytokine. Modification of the IFN? response impinges on the ability of other transcription factors regulated through ligands that bind to Toll receptors to regulate activation of ISG54. The altered responses in previously desensitized cells likely translate into changes in IFN? and Toll receptor-mediated responses in humans who are chronically treated with these cytokines.