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

View Article: PubMed Central - PubMed

ABSTRACT

Background: Dominant-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.

Methods: We 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.

Results: p53 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.

Conclusion: Our 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.

No MeSH data available.


Related in: MedlinePlus

p53 plays a pivotal role in inhibiting synovial inflammation. The inflammation of the synovium in RA significantly inhibits p53 expression or leads to p53 dysfunction. In turn, suppressed p53 results in increased secretion of IL-6, which further suppresses p53, probably by modulating Th17 differentiation. FLS fibroblast-like synoviocytes, IL interleukin, TNF tumor necrosis factor, TH17 IL-17 producing T helper, Treg regulatory T
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Fig6: p53 plays a pivotal role in inhibiting synovial inflammation. The inflammation of the synovium in RA significantly inhibits p53 expression or leads to p53 dysfunction. In turn, suppressed p53 results in increased secretion of IL-6, which further suppresses p53, probably by modulating Th17 differentiation. FLS fibroblast-like synoviocytes, IL interleukin, TNF tumor necrosis factor, TH17 IL-17 producing T helper, Treg regulatory T

Mentions: In addition to its regulation of the cell cycle and apoptosis, p53 might play a crucial role in suppressing synovial inflammation by interaction with signal transduction pathways and regulating the production of inflammatory mediators to control RA (Fig. 6). Therefore, p53 may be a key player in the complicated network of synovial inflammation, proliferation, and apoptosis, making it a potential target for gene and biologic therapeutic strategies in RA.Fig. 6


p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis
p53 plays a pivotal role in inhibiting synovial inflammation. The inflammation of the synovium in RA significantly inhibits p53 expression or leads to p53 dysfunction. In turn, suppressed p53 results in increased secretion of IL-6, which further suppresses p53, probably by modulating Th17 differentiation. FLS fibroblast-like synoviocytes, IL interleukin, TNF tumor necrosis factor, TH17 IL-17 producing T helper, Treg regulatory T
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5121977&req=5

Fig6: p53 plays a pivotal role in inhibiting synovial inflammation. The inflammation of the synovium in RA significantly inhibits p53 expression or leads to p53 dysfunction. In turn, suppressed p53 results in increased secretion of IL-6, which further suppresses p53, probably by modulating Th17 differentiation. FLS fibroblast-like synoviocytes, IL interleukin, TNF tumor necrosis factor, TH17 IL-17 producing T helper, Treg regulatory T
Mentions: In addition to its regulation of the cell cycle and apoptosis, p53 might play a crucial role in suppressing synovial inflammation by interaction with signal transduction pathways and regulating the production of inflammatory mediators to control RA (Fig. 6). Therefore, p53 may be a key player in the complicated network of synovial inflammation, proliferation, and apoptosis, making it a potential target for gene and biologic therapeutic strategies in RA.Fig. 6

View Article: PubMed Central - PubMed

ABSTRACT

Background: Dominant-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.

Methods: We 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.

Results: p53 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.

Conclusion: Our 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.

No MeSH data available.


Related in: MedlinePlus