Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, London W6 8LH, UK.
J Immunol. 2011 Nov 15;187(10):5357-62. doi: 10.4049/jimmunol.1100917. Epub 2011 Sep 30.
Excessive inflammation during bacterial and viral infections is destructive to the host and involves elevated production of proinflammatory cytokines. It is especially deleterious in organs with space constraints such as lung and the CNS. Indeed, a number of viruses that infect lungs, such as avian influenza virus, SARS-associated coronavirus, and respiratory syncytial virus, elicit a very high level of proinflammatory cytokines; however, it is unclear what triggers their production. In this study, we show that IL-17 commonly produced during viral infection specifically augments a proinflammatory response by directly synergizing with antiviral signaling. Costimulation of primary human fibroblasts with IL-17 greatly enhanced respiratory syncytial virus-induced or synthetic dsRNA-based viral mimic polyinosinic:polycytidylic acid-induced expression of proinflammatory genes without affecting expression of IFN-β-stimulated or IFN-stimulated genes. Knockdown of expression of known mediators of the antiviral signaling pathway revealed that the IL-17-poly(I:C) synergy depends on the presence of the transcriptional factors RelA and IFN regulatory factor 3 and IκB kinases. Moreover, this synergy was blocked by an IκB kinase inhibitor, BAY 11-7082. These findings shed light on the molecular mechanisms behind IL-17-dependent immunopathology observed in viral infections.
在细菌和病毒感染期间，过度的炎症对宿主具有破坏性，并涉及促炎细胞因子的升高产生。它在肺部和中枢神经系统等空间受限的器官中尤其有害。事实上，许多感染肺部的病毒，如禽流感病毒、SARS 相关冠状病毒和呼吸道合胞病毒，会引发非常高水平的促炎细胞因子；然而，尚不清楚是什么引发了它们的产生。在这项研究中，我们表明，IL-17 在病毒感染期间通常产生，通过与抗病毒信号直接协同作用，专门增强促炎反应。IL-17 与原代人成纤维细胞共刺激极大地增强了呼吸道合胞病毒诱导或基于合成 dsRNA 的病毒模拟物聚肌苷酸：聚胞苷酸诱导的促炎基因表达，而不影响 IFN-β 刺激或 IFN 刺激基因的表达。对抗病毒信号通路的已知介质表达的敲低揭示了 IL-17-聚（I:C）协同作用依赖于转录因子 RelA 和 IFN 调节因子 3 和 IκB 激酶的存在。此外，这种协同作用被 IκB 激酶抑制剂 BAY 11-7082 阻断。这些发现揭示了在病毒感染中观察到的 IL-17 依赖性免疫病理学背后的分子机制。
