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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 in FLS strongly controls different signal pathways to suppress proinflammatory cytokine production. a, b Different p53 status in FLS, including deficient p53, wild-type p53, and overexpressed p53, regulated the phosphorylation of p38, JNK, and ERK, as well as IkBα in the FLS. c p53 insufficiency in FLS promoted the inflammatory cytokine production, which was significantly blocked by different signal transduction inhibitors, similar to the effects of overexpressed p53 on the suppression of IL-6 production in FLS (Fig. 4d; Ad-p53 + IL-1β). Ad adenovirus, IL interleukin, TNF tumor necrosis factor
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Fig5: p53 in FLS strongly controls different signal pathways to suppress proinflammatory cytokine production. a, b Different p53 status in FLS, including deficient p53, wild-type p53, and overexpressed p53, regulated the phosphorylation of p38, JNK, and ERK, as well as IkBα in the FLS. c p53 insufficiency in FLS promoted the inflammatory cytokine production, which was significantly blocked by different signal transduction inhibitors, similar to the effects of overexpressed p53 on the suppression of IL-6 production in FLS (Fig. 4d; Ad-p53 + IL-1β). Ad adenovirus, IL interleukin, TNF tumor necrosis factor

Mentions: To address the mechanism of p53 controlling IL-6 production in the synovium, the upstream signal transduction pathways in the inflammatory process of RA were investigated. FLS with varying p53 status were prepared, including p53 knockdown, wild-type (wt) p53, and p53 overexpressed. Cells were then stimulated with IL-1β for 15 min and evaluated by Western blot analysis for NF-κB and MAPK pathways (Fig. 5a and b). p53 deficiency significantly augmented phosphorylation of IkBα, p38, JNK, and ERK in the FLS, while overexpression of p53 significantly reduced phosphorylation of the same proteins. The results strongly indicated that p53 inhibited inflammation-related signal transduction in FLS.Fig. 5


p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis
p53 in FLS strongly controls different signal pathways to suppress proinflammatory cytokine production. a, b Different p53 status in FLS, including deficient p53, wild-type p53, and overexpressed p53, regulated the phosphorylation of p38, JNK, and ERK, as well as IkBα in the FLS. c p53 insufficiency in FLS promoted the inflammatory cytokine production, which was significantly blocked by different signal transduction inhibitors, similar to the effects of overexpressed p53 on the suppression of IL-6 production in FLS (Fig. 4d; Ad-p53 + IL-1β). Ad adenovirus, IL interleukin, TNF tumor necrosis factor
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: p53 in FLS strongly controls different signal pathways to suppress proinflammatory cytokine production. a, b Different p53 status in FLS, including deficient p53, wild-type p53, and overexpressed p53, regulated the phosphorylation of p38, JNK, and ERK, as well as IkBα in the FLS. c p53 insufficiency in FLS promoted the inflammatory cytokine production, which was significantly blocked by different signal transduction inhibitors, similar to the effects of overexpressed p53 on the suppression of IL-6 production in FLS (Fig. 4d; Ad-p53 + IL-1β). Ad adenovirus, IL interleukin, TNF tumor necrosis factor
Mentions: To address the mechanism of p53 controlling IL-6 production in the synovium, the upstream signal transduction pathways in the inflammatory process of RA were investigated. FLS with varying p53 status were prepared, including p53 knockdown, wild-type (wt) p53, and p53 overexpressed. Cells were then stimulated with IL-1β for 15 min and evaluated by Western blot analysis for NF-κB and MAPK pathways (Fig. 5a and b). p53 deficiency significantly augmented phosphorylation of IkBα, p38, JNK, and ERK in the FLS, while overexpression of p53 significantly reduced phosphorylation of the same proteins. The results strongly indicated that p53 inhibited inflammation-related signal transduction in FLS.Fig. 5

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