Division of Rheumatology, Allergy, and Immunology, University of California, San Diego, La Jolla, CA 92093, United States.
Cell Immunol. 2011;271(2):342-9. doi: 10.1016/j.cellimm.2011.07.014. Epub 2011 Aug 10.
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.
I 型干扰素（IFN）反应在自身免疫中起着关键作用，是由先天受体结合和 IFN 调节因子（IRF）的激活诱导的。本研究探讨了 IRF3、IRF5 和 IRF7 在人 THP1 单核细胞细胞因子、趋化因子和基质金属蛋白酶表达中的作用和功能层次。通过靶向 IRF 敲低，评估基因表达、启动子激活和 mRNA 稳定性，以确定作为调节自身免疫性疾病患者 IFN 反应的潜在靶点的 IRF 的作用。IRF 在人类单核细胞中 I 型 IFN 基因表达的调节中发挥了独特的作用，特别是通过 IFN 刺激反应元件调节基因表达，而对传统的 AP-1 或 NF-κB 调节基因的转录没有贡献。IRF7 通过增加 IL-6 mRNA 的稳定性来调节 IL-6 基因的表达。IRF 对炎症的调节和 IFN 特征的诱导可能有助于自身免疫性疾病的发病机制，因此代表了新的治疗靶点。
