title: TBK1-targeted suppression of TRIF-dependent signaling pathway of toll-like receptor 3 by auranofin.
abstract: Toll-like receptors (TLRs) play an important role in induction of innate immune responses. The stimulation of TLRs by microbial components triggers two branches of downstream signaling pathways: myeloid differential factor 88 (MyD88)- and toll-interleukin-1 receptor domain-containing adapter inducing interferon-beta (TRIF)-dependent signaling pathways. Auranofin, a sulfur-containing gold compound (Au[I]), has been widely used for the treatment of rheumatoid arthritis. Since dysregulation of TLRs can lead to severe systemic inflammatory and joint destructive process in rheumatoid arthritis, auranofin-mediated modulation of TLR activation may have therapeutic potential against such diseases. Previously, we demonstrated that auranofin suppressed TLR4 signaling pathway by inhibiting TLR4 dimerization induced by LPS. Here, we examined the effect of auranofin on signal transduction via the TRIF-dependent pathway induced by a TLR3 agonist. Auranofin inhibited nuclear factor-kappaB and interferon (IFN) regulatory factor 3 (IRF3) activation induced by polyinosinic-polycytidylic acid (poly[I:C]). Auranofin inhibited poly[I:C]-induced phosphorylation of IRF3 as well as IFN-inducible genes such as IFN inducible protein-10. Furthermore, auranofin inhibited TBK1 kinase activity in vitro. All the results suggest that auranofin suppress TLR signaling at multiple steps.
authors.affiliation: Department of Medical Science, Soonchunhyang University, Asan, Korea.
authors.forename: Se-Jeong
authors.initials: SJ
authors.lastname: Park
authors.forename: A-Neum
authors.initials: AN
authors.lastname: Lee
authors.forename: Hyung-Sun
authors.initials: HS
authors.lastname: Youn
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001310:Auranofin / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D007369:Interferon Inducers / Q000037:antagonists & inhibitors / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D051196:Toll-Like Receptor 3 / Q000819:agonists / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018501:Antirheumatic Agents; D000998:Antiviral Agents; D001310:Auranofin; D054357:Chemokine CXCL10; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human; C498588:Tbk1 protein, mouse; C403191:TBK1 protein, human