Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
Mol Cell. 2019 May 16;74(4):801-815.e6. doi: 10.1016/j.molcel.2019.02.038. Epub 2019 Apr 2.
Interleukin-1 beta (IL-1β) is a pleiotropic mediator of inflammation and is produced in response to a wide range of stimuli. During infection, IL-1β production occurs in parallel with the onset of innate antimicrobial defenses, but the contribution of IL-1β signaling to cell-intrinsic immunity is not defined. Here, we report that exogenous IL-1β induces interferon regulatory factor 3 (IRF3) activation in human myeloid, fibroblast, and epithelial cells. IRF3 activation by IL-1β is dependent upon the DNA-sensing pathway adaptor, stimulator of interferon genes (STING), through the recognition of cytosolic mtDNA by cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS). IL-1β treatment results in interferon (IFN) production and activation of IFN signaling to direct a potent innate immune response that restricts dengue virus infection. This study identifies a new function for IL-1β in the onset or enhancement of cell-intrinsic immunity, with important implications for cGAS-STING in integrating inflammatory and microbial cues for host defense.
白细胞介素-1β（IL-1β）是炎症的多效介质，可响应广泛的刺激而产生。在感染过程中，IL-1β的产生与先天抗菌防御同时发生，但 IL-1β信号对细胞内在免疫的贡献尚不清楚。在这里，我们报告外源性 IL-1β可诱导人髓样细胞、成纤维细胞和上皮细胞中干扰素调节因子 3（IRF3）的激活。通过环鸟苷酸单磷酸（GMP）-AMP 合酶（cGAS）识别细胞质 mtDNA，IL-1β 对 STING（干扰素基因刺激物）的 DNA 感应途径衔接物的依赖性激活了 IRF3。IL-1β 处理可导致干扰素（IFN）的产生和 IFN 信号的激活，从而指导强大的先天免疫反应，限制登革热病毒感染。这项研究确定了 IL-1β在细胞内在免疫的起始或增强中的新功能，这对于 cGAS-STING 整合炎症和微生物信号以促进宿主防御具有重要意义。
