title: Targeting interferon regulatory factors to inhibit activation of the type I IFN response: implications for treatment of autoimmune disorders.
abstract: The type I interferon (IFN) response plays a critical role in autoimmunity and is induced by innate receptor ligation and activation of IFN-regulatory factors (IRF). The present study investigated the roles and functional hierarchy of IRF3, IRF5, and IRF7 in expression of cytokines, chemokines, and matrix metalloproteinases in human THP1 monocytic cells. Targeted IRF knockdown was followed by evaluation of gene expression, promoter activation, and mRNA stability to determine the role of IRF as potential targets for modulating IFN responses in patients with autoimmune diseases. IRF played a distinct role in regulation of type I IFN gene expression in human monocytic cells and specifically regulated gene expression through the IFN-stimulated response element, with no contribution to transcription of traditionally AP-1 or NF-kB regulated genes. IRF7 regulated IL-6 gene expression by increasing IL-6 mRNA stability. IRF regulation of inflammation and induction of the IFN signature might contribute to the pathogenesis of autoimmune diseases and therefore represent novel therapeutic targets.
authors.affiliation: Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, CA 92093, United States. ssweeney@ucsd.edu
authors.forename: Susan E
authors.initials: SE
authors.lastname: Sweeney
mesh_terms: D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology* / Q000628:therapy*; D002460:Cell Line; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000235:genetics; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C508600:IL6 protein, human; C494232:IRF3 protein, human; C431713:IRF5 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D015850:Interleukin-6; D034741:RNA, Small Interfering