4.0 Article

p53 Controls Autoimmune Arthritis via STAT-Mediated Regulation of the Th17 Cell/Treg Cell Balance in Mice

Journal

ARTHRITIS AND RHEUMATISM
Volume 65, Issue 4, Pages 949-959

Publisher

WILEY-BLACKWELL
DOI: 10.1002/art.37841

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Funding

  1. National Research Foundation of Korea
  2. Ministry of Education, Science, and Technology [2010-0020767]
  3. National Project for Personalized Genomic Medicine
  4. Ministry for Health and Welfare, Republic of Korea [A111218-PG01]
  5. National Research Foundation of Korea [2010-0020767] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Objective To investigate the connection between p53 and interleukin-17producing 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 immunoprecipitationWestern 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. Conclusion 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.

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