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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

Nutlin-3 attenuated arthritis and decreased IL-6 production in Lewis AIA rats. Lewis rats were immunized with complete Freund’s adjuvant, and received Nutlin-3, dimethyl sulfoxide (DMSO), or phosphate-buffered saline (PBS) from day 8 to day 12 after immunization. Arthritis scores were assessed every 3 days. a The mean arthritis scores. Nutlin significantly decreased arthritis, compared to DMSO (p = 0.16 and 0.02, respectively, on day (d)13 and day 21). b Severity of inflammation was calculated by subtracting the volume of hind paw swelling between day 21 and day 8 after immunization (p = 0.04, Nutlin versus DMSO) and the body weight of the Nutlin group has a tendency to increase (p = 0.14, Nutlin versus DMSO). c Interleukin-6 (IL-6) levels in the serum of the Nutlin group were significantly decreased compared to those in the DMSO and PBS groups (p = 0.01 and 0.04, respectively). d IL-6 level in the joint (p = 0.09, Nutlin versus DMSO; p = 0.19, Nutlin versus PBS). e Nutlin-3 decreased infiltration of inflammatory cells into the synovial tissue and bone erosion in AIA rats. Infiltration of inflammatory cells into the synovial tissue and pannus formation were observed in DMSO and PBS group, but not in the Nutlin group. *p < 0.01
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Fig1: Nutlin-3 attenuated arthritis and decreased IL-6 production in Lewis AIA rats. Lewis rats were immunized with complete Freund’s adjuvant, and received Nutlin-3, dimethyl sulfoxide (DMSO), or phosphate-buffered saline (PBS) from day 8 to day 12 after immunization. Arthritis scores were assessed every 3 days. a The mean arthritis scores. Nutlin significantly decreased arthritis, compared to DMSO (p = 0.16 and 0.02, respectively, on day (d)13 and day 21). b Severity of inflammation was calculated by subtracting the volume of hind paw swelling between day 21 and day 8 after immunization (p = 0.04, Nutlin versus DMSO) and the body weight of the Nutlin group has a tendency to increase (p = 0.14, Nutlin versus DMSO). c Interleukin-6 (IL-6) levels in the serum of the Nutlin group were significantly decreased compared to those in the DMSO and PBS groups (p = 0.01 and 0.04, respectively). d IL-6 level in the joint (p = 0.09, Nutlin versus DMSO; p = 0.19, Nutlin versus PBS). e Nutlin-3 decreased infiltration of inflammatory cells into the synovial tissue and bone erosion in AIA rats. Infiltration of inflammatory cells into the synovial tissue and pannus formation were observed in DMSO and PBS group, but not in the Nutlin group. *p < 0.01

Mentions: To test the efficacy of p53 in treating inflammatory arthritis, AIA in the Lewis rat model was used. Intraperitoneal injection of Nutlin-3, a p53 activator, ameliorated arthritis dramatically, including a significant decrease in arthritis scores and joint swelling relative to the vehicle-treated group (p < 0.05; Fig. 1a and b). There was a trend for increased body weight in the Nutlin group compared to that in the vehicle group (Fig. 1b). Histopathologic analysis indicated that the synovium in Nutlin-treated rats was less inflamed than those treated with vehicle or PBS (Fig. 1e).Fig. 1


p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis
Nutlin-3 attenuated arthritis and decreased IL-6 production in Lewis AIA rats. Lewis rats were immunized with complete Freund’s adjuvant, and received Nutlin-3, dimethyl sulfoxide (DMSO), or phosphate-buffered saline (PBS) from day 8 to day 12 after immunization. Arthritis scores were assessed every 3 days. a The mean arthritis scores. Nutlin significantly decreased arthritis, compared to DMSO (p = 0.16 and 0.02, respectively, on day (d)13 and day 21). b Severity of inflammation was calculated by subtracting the volume of hind paw swelling between day 21 and day 8 after immunization (p = 0.04, Nutlin versus DMSO) and the body weight of the Nutlin group has a tendency to increase (p = 0.14, Nutlin versus DMSO). c Interleukin-6 (IL-6) levels in the serum of the Nutlin group were significantly decreased compared to those in the DMSO and PBS groups (p = 0.01 and 0.04, respectively). d IL-6 level in the joint (p = 0.09, Nutlin versus DMSO; p = 0.19, Nutlin versus PBS). e Nutlin-3 decreased infiltration of inflammatory cells into the synovial tissue and bone erosion in AIA rats. Infiltration of inflammatory cells into the synovial tissue and pannus formation were observed in DMSO and PBS group, but not in the Nutlin group. *p < 0.01
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Nutlin-3 attenuated arthritis and decreased IL-6 production in Lewis AIA rats. Lewis rats were immunized with complete Freund’s adjuvant, and received Nutlin-3, dimethyl sulfoxide (DMSO), or phosphate-buffered saline (PBS) from day 8 to day 12 after immunization. Arthritis scores were assessed every 3 days. a The mean arthritis scores. Nutlin significantly decreased arthritis, compared to DMSO (p = 0.16 and 0.02, respectively, on day (d)13 and day 21). b Severity of inflammation was calculated by subtracting the volume of hind paw swelling between day 21 and day 8 after immunization (p = 0.04, Nutlin versus DMSO) and the body weight of the Nutlin group has a tendency to increase (p = 0.14, Nutlin versus DMSO). c Interleukin-6 (IL-6) levels in the serum of the Nutlin group were significantly decreased compared to those in the DMSO and PBS groups (p = 0.01 and 0.04, respectively). d IL-6 level in the joint (p = 0.09, Nutlin versus DMSO; p = 0.19, Nutlin versus PBS). e Nutlin-3 decreased infiltration of inflammatory cells into the synovial tissue and bone erosion in AIA rats. Infiltration of inflammatory cells into the synovial tissue and pannus formation were observed in DMSO and PBS group, but not in the Nutlin group. *p < 0.01
Mentions: To test the efficacy of p53 in treating inflammatory arthritis, AIA in the Lewis rat model was used. Intraperitoneal injection of Nutlin-3, a p53 activator, ameliorated arthritis dramatically, including a significant decrease in arthritis scores and joint swelling relative to the vehicle-treated group (p < 0.05; Fig. 1a and b). There was a trend for increased body weight in the Nutlin group compared to that in the vehicle group (Fig. 1b). Histopathologic analysis indicated that the synovium in Nutlin-treated rats was less inflamed than those treated with vehicle or PBS (Fig. 1e).Fig. 1

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-1&beta;, tumor necrosis factor (TNF)-&alpha; 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