arthritis 1-9

Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis

H. Nie, Y. X. Zheng, R. S. Li, T. B. Guo, D. Y. He, L. Fang, X. B. Liu, L. B. Xiao, X. Chen, B. Wan, et al.

Nature Medicine.2013 Mar;19(3):322-328.

Abstract: Regulatory T (T-reg) cells suppress autoimmune disease, and impaired T-reg cell function is associated with rheumatoid arthritis. Here we demonstrate that forkhead box P3 (FOXP3) transcriptional activity and, consequently, T-reg cell suppressive function are regulated by phosphorylation at Ser418 in the C-terminal DNA-binding domain. In rheumatoid arthritis-derived T-reg cells, the Ser418 site was specifically dephosphorylated by protein phosphatase 1 (PP1), whose expression and enzymatic activity were induced in the inflamed synovium by tumor necrosis factor alpha (TNF-alpha), leading to impaired T-reg cell function. Moreover, TNF-alpha-induced T-reg cell dysfunction correlated with increased numbers of interleukin-17 (IL-17)(+) and interferon-gamma (IFN-gamma)(+)CD4(+) T cells within the inflamed synovium in rheumatoid arthritis. Treatment with a INF-alpha-specific antibody restored T-reg cell function in subjects with rheumatoid arthritis, which was associated with decreased PP1 expression and increased FOXP3 phosphorylation in T-reg cells. Thus, TNF-alpha controls the balance between T-reg cells and pathogenic T(H)17 and T(H)1 cells in the synovium of individuals with rheumatoid arthritis through FOXP3 dephosphorylation.

*Times cited: 1

Keywords: nf-kappa-b, therapy, acetylation, cooperation, cytokines, colitis, binding, genes


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