title: p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis.
abstract: Dominant-negative somatic mutations of p53 has been identified in the synovium of patients with rheumatoid arthritis (RA), in which interleukin (IL)-6 has been established as a pivotal inflammatory cytokine. The aim of this study was to clarify the significance of p53 in the longstanding inflammation in RA by modulating IL-6.
  
  
  
  We established adjuvant-induced arthritis (AIA) in Lewis rats and treated them with p53 activator, and then analyzed the histopathology of the synovium and IL-6 expression. Human fibroblast-like synoviocytes (FLS) were cultured and transfected with p53-siRNA or transduced with adenovirus (Ad)-p53, and then assessed with MTT, TUNEL staining, and luciferase assay. IL-1β, tumor necrosis factor (TNF)-α and IL-17 were used to stimulate FLS, and subsequent IL-6 expression as well as relevant signal pathways were explored.
  
  
  
  p53 significantly reduced synovitis as well as the IL-6 level in the AIA rats. It controlled cell cycle arrest and proliferation, but not apoptosis. Proinflammatory cytokines inhibited p53 expression in FLS, while p53 significantly suppressed the production of IL-6. Furthermore, IL-6 expression in p53-deficient FLS was profoundly reduced by NF-kappaB, p38, JNK, and ERK inhibitors.
  
  
  
  Our findings reveal a novel function of p53 in controlling inflammatory responses and suggest that p53 abnormalities in RA could sustain and accelerate synovial inflammation mainly through IL-6. p53 may be a key modulator of IL-6 in the synovium and plays a pivotal role in suppressing inflammation by interaction with the signal pathways in RA-FLS. Interfering with the p53 pathway could therefore be an effective strategy to treat RA.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Basic Science Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
authors.forename: Huihua
authors.initials: H
authors.lastname: Li
authors.affiliation: Basic Science Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Muyuan
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Leting
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Basic Science Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
authors.forename: Dexian
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Fulin
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China. youxinpumch@hotmail.com.
authors.forename: Xin
authors.identifier: 0000-0002-3546-1291
authors.initials: X
authors.lastname: You
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D000070918:Synoviocytes / Q000276:immunology / Q000378:metabolism; D013585:Synovitis / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000276:immunology* / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016159:Tumor Suppressor Protein p53
keywords: Fibroblast-like synoviocytes; Interleukin-6; Rheumatoid arthritis; Signal transduction; p53