title: p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice.
abstract: OBJECTIVE
  To investigate the connection between p53 and interleukin-17-producing Th17 cell/Treg cell balance in rheumatoid arthritis (RA).
  
  
  METHODS
  Th17 cell and Treg cell frequencies were analyzed by flow cytometry, and cytokine levels in the supernatant were determined using enzyme-linked immunosorbent assays. The expression of transcription factors was analyzed by immunostaining and Western blotting, and the interactions between p53 and STAT-3 or STAT-5 were determined by immunoprecipitation-Western blot analysis. A p53 agonist was administered in the collagen-induced arthritis (CIA) model, and the effects in vivo were determined.
  
  
  RESULTS
  CD4+ T cells from p53-/- mice decreased the activity of STAT-5, lowered the level of phosphorylated STAT-5, and compromised Treg cell differentiation. The protein p53 bound STAT-5 directly, and this interaction was enhanced with increasing p53 activity. Under inflammatory conditions, p53 suppressed Th17 cell differentiation and skewed T cells toward Treg cell differentiation through the activation of STAT-5 signaling cascades. In mice with CIA, injection of a p53 overexpression vector or an antagonist of Mdm2 had the effect of controlling arthritis development in vivo. The regulatory effect of p53 was recapitulated in the cells of RA patients, with more pronounced suppression due to the repressed status of p53 in RA.
  
  
  CONCLUSIONS
  We demonstrated a link between p53-mediated and STAT-mediated regulation of Th17 cells/Treg cells in RA. Our results suggest that factors involved in this pathway might constitute novel therapeutic targets for the treatment of RA.
authors.affiliation: Rheumatism Research Center, Catholic Institute of Medical Sciences, Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Jin-Sil
authors.initials: JS
authors.lastname: Park
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Lim
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Jun-Geol
authors.initials: JG
authors.lastname: Ryu
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Moon
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Jae-Kyeong
authors.initials: JK
authors.lastname: Byun
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Sue-Yun
authors.initials: SY
authors.lastname: Hwang
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000628:therapy; D016022:Case-Control Studies; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D016159:Tumor Suppressor Protein p53