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Thiolat, Allan; Biton, Jérôme; Decker, Patrice; Semerano, Luca; Mc, Boissier; Ym, Pers; Plence, P; Bessis, Natacha

doi:10.1002/art.38717

Cited by 1 publication

(1 citation statement)

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“…Treatment with the anti-IL-6 receptor antibody tocilizumab induces a significant decrease in the percentage of TH17 cells and an increase in the percentage of Treg cells in RA patients, resulting in a correction of the TH17/Treg cell imbalance [37, 39]. Although controversial results suggest unaffected TH17 cells with upregulated Treg cells after anti-IL-6 receptor treatment, there is a trend that TH17 cells are decreased [40–42]. So, combined with our results, we assume that p53 deficiency in RA promotes arthritic inflammation through upregulation of IL-6, which exerts its pivotal role by converting Tregs to TH17 cells.…”

Section: Discussionmentioning

confidence: 99%

p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis

Zhang¹,

Shi

et al. 2016

Arthritis Res Ther

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BackgroundDominant-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.MethodsWe 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.Resultsp53 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.ConclusionOur 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.

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