title: Double-stranded RNA upregulates the expression of inflammatory mediators in human aortic valve cells through the TLR3-TRIF-noncanonical NF-κB pathway.
abstract: Calcific aortic valve disease is a chronic inflammatory condition, and the inflammatory responses of aortic valve interstitial cells (AVICs) play a critical role in the disease progression. Double-stranded RNA (dsRNA) released from damaged or stressed cells is proinflammatory and may contribute to the mechanism of chronic inflammation observed in diseased aortic valves. The objective of this study is to determine the effect of dsRNA on AVIC inflammatory responses and the underlying mechanism. AVICs from normal human aortic valves were stimulated with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of dsRNA. Poly(I:C) increased the production of IL-6, IL-8, monocyte chemoattractant protein-1, and ICAM-1. Poly(I:C) also induced robust activation of ERK1/2 and NF-κB. Knockdown of Toll-like receptor 3 (TLR3) or Toll-IL-1 receptor domain-containing adapter-inducing IFN-β (TRIF) suppressed ERK1/2 and NF-κB p65 phosphorylation and reduced inflammatory mediator production induced by poly(I:C). Inhibition of NF-κB, not ERK1/2, reduced inflammatory mediator production in AVICs exposed to poly(I:C). Interestingly, inhibition of NF-κB by prevention of p50 migration failed to suppress inflammatory mediator production. NF-κB p65 intranuclear translocation induced by the TLR4 agonist was reduced by inhibition of p50 migration; however, poly(I:C)-induced p65 translocation was not, although the p65/p50 heterodimer is present in AVICs. Poly(I:C) upregulates the production of multiple inflammatory mediators through the TLR3-TRIF-NF-κB pathway in human AVICs. The NF-κB activated by dsRNA appears not to be the canonical p65/p50 heterodimers.
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and.|Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and.|Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and.
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.affiliation: Department of Surgery, University of Colorado Denver, Aurora, Colorado; and xianzhong.meng@ucdenver.edu.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology; D001021:Aortic Valve / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D006349:Heart Valve Diseases / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D061205:Vascular Calcification / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018836:Inflammation Mediators; D016328:NF-kappa B; D012330:RNA, Double-Stranded; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3
keywords: NF-κB; TLR3; TRIF; aortic valve interstitial cells; inflammation