SIGNALING IN CELLS CHRONICALLY EXPOSED TO INTERFERON BETA (NMSS)

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 摘要：在过去的十年里，关于干扰素和其他细胞因子通过JAK/STAT途径激活或下调即刻早期基因的机制已经获得了丰富的知识。然而，与那些已经对这些细胞因子的作用脱敏并随后重新敏化的细胞相比，关于纳米细胞中干扰素激活的基因表达的信息很少，从而在临床环境中模拟重复给予干扰素。在纳米细胞中，ISG54基因是通过干扰素刺激的ISGF3的形成而激活的，ISGF3是由P48(IRF9)和酪氨酸磷酸化的STAT1和STAT2组成的异源三聚体DNA结合复合体，它结合干扰素刺激反应元件(ISRE)。相反，在先前脱敏的细胞中，干扰素？弱刺激缺乏酪氨酸磷酸化STAT1的ISGF3样复合体的组装，即使ISG54 mRNA的诱导与Nanve细胞相同。缺乏STAT1酪氨酸磷酸化和DNA结合是由于蛋白酪氨酸磷酸酶TC-PTP活性增加所致。尽管在先前脱敏的细胞中，干扰素刺激的ISGF3的形成减少，但内毒素诱导ISG54表达的能力大大增强，可能是通过依赖TLR4/IRF3的信号通路。依赖ISRE的早期反应基因的激活在以前对这种细胞因子脱敏的细胞中有很大的不同。干扰素的修饰？反应影响其他转录因子的能力，这些转录因子通过与Toll受体结合的配体来调节ISG54的激活。先前脱敏细胞的反应改变很可能转化为干扰素？在长期使用这些细胞因子治疗的人类中，Toll受体介导的反应。

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.