title: A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.
abstract: The main etiopathogenesis of rheumatoid arthritis (RA) is overexpressed inflammatory cytokines and tissue injury mediated by persistent NF-κB activation. MicroRNAs widely participate in the regulation of target gene expression and play important roles in various diseases. Here, we explored the mechanisms of microRNAs in RA. We found that microRNA (miR)-10a was downregulated in the fibroblast-like synoviocytes (FLSs) of RA patients compared with osteoarthritis (OA) controls, and this downregulation could be triggered by TNF-α and IL-1β in an NF-κB-dependent manner through promoting the expression of the YingYang 1 (YY1) transcription factor. Downregulated miR-10a could accelerate IκB degradation and NF-κB activation by targeting IRAK4, TAK1 and BTRC. This miR-10a-mediated NF-κB activation then significantly promoted the production of various inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-8, and MCP-1, and matrix metalloproteinase (MMP)-1 and MMP-13. In addition, transfection of a miR-10a inhibitor accelerated the proliferation and migration of FLSs. Collectively, our data demonstrates the existence of a novel NF-κB/YY1/miR-10a/NF-κB regulatory circuit that promotes the excessive secretion of NF-κB-mediated inflammatory cytokines and the proliferation and migration of RA FLSs. Thus, miR-10a acts as a switch to control this regulatory circuit and may serve as a diagnostic and therapeutic target for RA treatment.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Mu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Tonglie
authors.initials: T
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Cun
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Shu
authors.affiliation: Department of Pharmacogenomics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Weina
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Wangqian
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Clinical Immunology and Rheumatology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jinkang
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Institute of Orthopedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Luyu
authors.initials: L
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Shuning
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Human Anatomy, Histology, and Embryology, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaohang
authors.initials: X
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biopharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D001665:Binding Sites; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000235:genetics*; D013583:Synovial Membrane / Q000378:metabolism; D000070918:Synoviocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D050986:YY1 Transcription Factor / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D053592:Interleukin-1 Receptor-Associated Kinases; D053583:Interleukin-1beta; D020930:MAP Kinase Kinase Kinases; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; D050986:YY1 Transcription Factor; D000099151:MAP Kinase Kinase Kinase 7; C491341:LILRB2 protein, human; C507773:IRAK4 protein, human
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