Toll-like receptor 3 (TLR3) is a sensor of endogenous cell necrosis during the process of acute inflammation. Interleukin (IL)-1 receptor antagonist (IL-1Ra) is an anti-inflammatory cytokine and can negatively regulate the pathogenesis of inflammation. However, whether and how activation of TLR3 can regulate IL-1Ra expression has not been clarified. Here, we show that poly(I:C) induces IL-1Ra expression in primarily cultured human fibroblast-like synoviocytes and other types of cells. Induction of IL-1Ra by poly(I:C) was dependent on TLR3, but was independent of melanoma differentiation-­associated protein 5 or retinoic acid-inducible gene I. Interferon regulatory factor 3 (IRF3) directly binds to the IL-1Ra promoter and promotes IL-1Ra expression in response to poly(I:C) stimulation. Induction of IL-1Ra by poly(I:C) was abolished by the inhibition of the NF-κB signaling, attenuated by the inhibition of the PI3K-Akt signaling, enhanced by inhibition of the ERK1/2 or MSK1/2 activation, but was independent of the p38 MAPK signaling. Treatment with poly(I:C) or Sendai virus elevated the levels of serum IL-1Ra in wild-type, but not in TLR3^–/– or IRF3^–/– mice. Our findings may provide new insights into the intrinsic anti-inflammatory function of TLR3 and double-stranded RNA-induced IL-Ra expression by TLR3 and its regulation.
J Innate Immun

中文翻译：

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Toll样受体3的激活通过激活干扰素调节因子3诱导白介素1受体拮抗剂的表达。

Toll样受体3（TLR3）是急性炎症过程中内源性细胞坏死的传感器。白介素（IL）-1受体拮抗剂（IL-1Ra）是一种抗炎细胞因子，可以消极调节炎症的发病机理。然而，尚未阐明TLR3的激活是否以及如何调节IL-1Ra的表达。在这里，我们表明，poly（I：C）在主要培养的人成纤维样滑膜细胞和其他类型的细胞中诱导IL-1Ra表达。聚（I：C）诱导IL-1Ra依赖于TLR3，但不依赖于黑色素瘤分化相关蛋白5或视黄酸诱导基因I。干扰素调节因子3（IRF3）直接与IL-1Ra启动子结合并响应poly（I：C）刺激促进IL-1Ra表达。聚（I：C）通过抑制NF-κB信号而消除，通过抑制PI3K-Akt信号而减弱，通过抑制ERK1 / 2或MSK1 / 2激活而增强，但与p38 MAPK信号无关。用Poly（I：C）或仙台病毒治疗可提高野生型的血清IL-1Ra水平，但不会提高TLR3的血清IL-1Ra水平^{– / –}或IRF3 ^{– / –}小鼠。我们的发现可能为TLR3固有的抗炎功能以及TLR3对其调控的双链RNA诱导的IL-Ra表达提供新的见解。
免疫学杂志