RRC ID 58372
Author Liu Y, Mo CF, Luo XY, Li H, Guo HJ, Sun H, Hu S, Li LM, Wang YT, Yang SX, Chang S, Zou Q.
Title Activation of Toll-Like Receptor 3 Induces Interleukin-1 Receptor Antagonist Expression by Activating the Interferon Regulatory Factor 3.
Journal J Innate Immun
Abstract 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.
Volume 12(4)
Pages 304-320
Published 2020-1-1
DOI 10.1159/000504321
PII 000504321
PMID 31865314
PMC PMC7383292
MeSH Animals Cell Line Humans Inflammation / chemically induced Inflammation / genetics Inflammation / immunology Interferon Regulatory Factor-3 / genetics Interleukin 1 Receptor Antagonist Protein / genetics Interleukin 1 Receptor Antagonist Protein / immunology* Mice Mice, Knockout Poly I-C / pharmacology Toll-Like Receptor 3 / genetics Toll-Like Receptor 3 / immunology*
IF 4.932
Times Cited 1
Mice RBRC00858