2. Academic Validation
  3. FC-99 reduces macrophage tenascin-C expression by upregulating miRNA-494 in arthritis

FC-99 reduces macrophage tenascin-C expression by upregulating miRNA-494 in arthritis

  • Int Immunopharmacol. 2020 Feb:79:106105. doi: 10.1016/j.intimp.2019.106105.
Haiyan Zhu 1,  Juanhua Fu 1,  Sheng Chen 2,  Xiaoqin Li 1,  Huaping Liang 3,  Yayi Hou 4,  Huan Dou 5
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
  • 2 Nangjing Stomatological Hospital, Medical School of Nanjing University, Nanjing 210008, China.
  • 3 State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, The Army Medical University, Chongqing 400042, China. Electronic address: [email protected].
  • 4 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China. Electronic address: [email protected].
  • 5 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China. Electronic address: [email protected].
PMID: 31881378 DOI: 10.1016/j.intimp.2019.106105
Abstract

The excessive production of inflammatory mediators by inflammatory cells contributes to the pathogenesis of rheumatoid arthritis. Tenascin-C (TN-C) is expressed in rheumatoid joint, and is associated with levels of inflammatory mediators. FC-99 (N1-[(4-methoxy)methyl]-4-methyl-1,2-Benzenediamine), a novel 1,2-benzenediamine derivative, was previously reported to block the prolonged expression of key rheumatoid arthritis inflammatory cytokines and relieve zymosan-induced joint inflammation. However, the specific mechanism is unknown. This study aimed to examine the effects of FC-99 on TN-C expression and inflammation and investigate its possible molecular mechanism. The results showed that FC-99 treatment reduced the high expression of TN-C in ankle joints of arthritis mice. Besides, FC-99 reduced the increased number of macrophages in arthritis mice, while did not change the number of synovioblasts. Concomitantly, expression of TN-C in synovial fibroblasts exhibited no difference between control and ZIA groups, and was not apparently altered following FC-99 treatment, while FC-99 decreased TN-C expression in macrophages both in vivo and in vitro. Meanwhile, TargetScan and luciferase assays indicated that TN-C was negatively regulated by miR-494. Transfection assay further demonstrated that FC-99 inhibited TN-C by targeting miR-494. Furthermore, the reduction of miR-494 mimic on expression of TN-C was associated with NF-κB pathway. Similarly, the down-regulation of FC-99 on TN-C was considerably decreased when NF-κB pathway was inhibited. These results indicated that FC-99 relieved macrophages inflammation via the miR-494/TN-C/NF-κB pathway, finally leading to the relief of inflammation in arthritis. The findings suggested that FC-99 might be a potential therapeutic candidate for the treatment of rheumatoid arthritis.

Keywords

FC-99; Macrophages; MiRNA-494; Tenascin-C; Zymosan-induced arthritis.

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