Journal
JOURNAL OF INNATE IMMUNITY
Volume 12, Issue 4, Pages 304-320Publisher
KARGER
DOI: 10.1159/000504321
Keywords
Poly(I; C); Toll-like receptor 3; Interleukin-1 receptor antagonist; Interferon regulatory factor 3; Human fibroblast-like synoviocytes
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Funding
- National Natural Science Foundation of China [81302786, 81402944, 81871300]
- Sichuan Science and TechnologyProgram [2018JY0440, 2018JY0481]
- Scientific Research Fund of Sichuan Provincial Education Department [18ZA0143]
- State Key Laboratory of Phytochemistry and Plant Resources in West China [P2018-KF03]
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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-kappa B 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.
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