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Journal

p53 controls autoimmune arthritis via the STAT3/STAT5-mediated regulation of the Th17�Treg balance

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Published:25th Mar 2020
Objective: To investigate the connection between p53 and interleukin (IL)-17�producing helper T (Th17)/regulatory T (Treg) balance in rheumatoid arthritis (RA). Methods: Th17 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 STAT3 or STAT5 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 STAT5, lowered the level of phosphorylated STAT5, and compromised Treg differentiation. p53 binds STAT5 directly, and this interaction was enhanced with increasing p53 activity. Under inflammatory conditions, p53 suppressed Th17 cell differentiation and skewed T cells toward Treg differentiation through the activation of STAT5 signaling cascades. In CIA mice, injection of a p53 overexpression vector or an antagonist of murine double minute 2 (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 the p53 and STAT-mediated Th17/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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