SIGNALING IN CELLS CHRONICALLY EXPOSED TO INTERFERON BETA (NMSS)

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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.