Activation of Toll-Like Receptor 3 Induces Interleukin-1 Receptor Antagonist Expression by Activating the Interferon Regulatory Factor 3

• Published in: Journal of innate immunity Vol. 12; no. 4; pp. 304 - 320
• Main Authors: Liu, Yang, Mo, Chun-Fen, Luo, Xing-Yan, Li, Hua, Guo, Hui-Jie, Sun, Hai, Hu, Song, Li, Li-Mei, Wang, Yan-Tang, Yang, Shu-Xia, Chang, Shan, Zou, Qiang
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.07.2020; Karger Publishers
• Subjects: human fibroblast-like synoviocytes; interferon regulatory factor 3; interleukin-1 receptor antagonist; poly(i:c); Research Article; toll-like receptor 3; Human fibroblast-like synoviocytes; Interferon regulatory factor 3; Poly(I:C); Toll-like receptor 3; Interleukin-1 receptor antagonist
• ISSN: 1662-811X; 1662-8128
• DOI: 10.1159/000504321

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.