title: Adenovirus-Mediated Small Interfering RNA Targeting TAK1 Ameliorates Joint Inflammation with Collagen-Induced Arthritis in Mice.
abstract: Transforming growth factor β-activated kinase-1 (TAK1) is a key upstream kinase in cell signaling during inflammation, which regulates the expression of inflammatory mediators. Small interfering RNA (siRNA) against TAK1 offers promise as a potential therapeutic strategy in immune-mediated inflammatory disorder including rheumatoid arthritis. Here, we are to evaluate the therapeutic effects of intra-articular administration of adenoviral-mediated siRNA against TAK1 (ad-siRNA-TAK1) on collagen-induced arthritis (CIA) in mice. Ad-siRNA-TAK1 was constructed. The murine RAW 264.7 macrophages were infected with ad-siRNA-TAK1, and the silencing specificity of TAK1 was assessed by quantitative polymerase chain reaction (PCR) and western blot. DBA/1 mice were injected intra-articularly with ad-siRNA-TAK1. Development and severity of arthritis was assessed histologically. Synovial inflammation and bone destruction were determined by hematoxylin and eosin (HE) staining. Articular and serum concentrations of tumor necrosis factor-α, interleukin-1, and interleukin-6 were determined using enzyme-linked immunosorbent assay. Levels of phosphorylated p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) were detected by western blot. In vitro, ad--siRNA-TAK1 efficiently inhibited the expression of TAK1 at both mRNA and protein levels. In vivo, intra-articular injection of ad-siRNA-TAK1 efficiently alleviated joint inflammation, decreased the expression of pro-inflammatory mediators, and suppressed JNK pathways. Our results demonstrate the efficiency of ad--siRNA-TAK1 in controlling joint inflammation of CIA, which is associated with the suppression of the expression of pro-inflammatory cytokines and JNK activation.
authors.affiliation: Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou, 318000, Zhejiang, China.
authors.forename: Xinjing
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou, 318000, Zhejiang, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicine, Yingzhou District Second People's Hospital, Ningbo, 315000, China.
authors.forename: Guoju
authors.initials: G
authors.lastname: Lv
authors.affiliation: Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou, 318000, Zhejiang, China.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou, 318000, Zhejiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou, 318000, Zhejiang, China.
authors.forename: Xuanrong
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Medicine, Yingzhou District Second People's Hospital, Ningbo, 315000, China. tz52xjw@163.com.
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Xie
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D003094:Collagen; D016207:Cytokines / Q000187:drug effects; D020868:Gene Silencing; D007249:Inflammation / Q000188:drug therapy / Q000517:prevention & control*; D007270:Injections, Intra-Articular; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects; D007596:Joints / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D000067996:RAW 264.7 Cells; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D003094:Collagen; D016207:Cytokines; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D000099151:MAP Kinase Kinase Kinase 7
keywords: TAK1; collagen-induced arthritis; cytokines; signal pathways