title: Krüppel-Like Factor 4 Is a Regulator of Proinflammatory Signaling in Fibroblast-Like Synoviocytes through Increased IL-6 Expression.
abstract: Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA). Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients. In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.
authors.affiliation: Department of Basic Medical Sciences, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, China; Institute of Tumor Research, School of Medicine, Taizhou University, Taizhou 318000, China.
authors.forename: Xinjing
authors.identifier: 0000-0002-8010-6846
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Basic Medical Sciences, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, China.
authors.forename: Jie
authors.identifier: 0000-0001-7962-0840
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Orthopedics and Sports Medicine, Taizhou Municipal Hospital, Taizhou 318000, China.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Basic Medical Sciences, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, China.
authors.forename: Yongfeng
authors.identifier: 0000-0002-1360-9240
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Basic Medical Sciences, School of Medicine, Taizhou University, Taizhou, Zhejiang 318000, China.
authors.forename: Xuanrong
authors.identifier: 0000-0002-8838-3792
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Cardiology, Yingzhou District Second People's Hospital, Ningbo 315000, China.
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Yingzhou District Second People's Hospital, Ningbo 315000, China.
authors.forename: Guoju
authors.initials: G
authors.lastname: Lv
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha