Adenovirus-Mediated Small Interfering RNA Targeting TAK1 Ameliorates Joint Inflammation with Collagen-Induced Arthritis in Mice

• Published in: Inflammation Vol. 40; no. 3; pp. 894 - 903
• Main Authors: Luo, Xinjing, Chen, Yongfeng, Lv, Guoju, Zhou, Zhidong, Chen, Jie, Mo, Xuanrong, Xie, Jiangwen
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2017; Springer Nature B.V
• Subjects: Adenoviridae - genetics; Animals; Arthritis; Arthritis, Rheumatoid - chemically induced; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - prevention & control; Biomedical and Life Sciences; Biomedicine; c-Jun protein; Collagen; Cytokines; Cytokines - drug effects; Enzyme-linked immunosorbent assay; Extracellular signal-regulated kinase; Gene Silencing; Immunology; Inflammation; Inflammation - drug therapy; Inflammation - prevention & control; Inflammatory diseases; Injections, Intra-Articular; Interleukin 1; Interleukin 6; Internal Medicine; JNK Mitogen-Activated Protein Kinases - drug effects; JNK protein; Joints - pathology; Kinases; Macrophages; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; Mice; mRNA; Original Article; Pathology; Pharmacology/Toxicology; Polymerase chain reaction; RAW 264.7 Cells; Rheumatoid arthritis; Rheumatology; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - pharmacology; siRNA; TAK1 protein; Transcription factors; collagen-induced arthritis; signal pathways; cytokines; TAK1
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-017-0534-4

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.