Title |
p53 predominantly regulates IL-6 production and suppresses synovial inflammation in fibroblast-like synoviocytes and adjuvant-induced arthritis
|
---|---|
Published in |
Arthritis Research & Therapy, November 2016
|
DOI | 10.1186/s13075-016-1161-4 |
Pubmed ID | |
Authors |
Ting Zhang, Huihua Li, Juan Shi, Sha Li, Muyuan Li, Lei Zhang, Leting Zheng, Dexian Zheng, Fulin Tang, Xuan Zhang, Fengchun Zhang, Xin You |
Abstract |
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. 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. 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. 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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 44 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Master | 9 | 20% |
Student > Ph. D. Student | 7 | 16% |
Researcher | 5 | 11% |
Other | 4 | 9% |
Student > Doctoral Student | 2 | 5% |
Other | 5 | 11% |
Unknown | 12 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 10 | 23% |
Biochemistry, Genetics and Molecular Biology | 7 | 16% |
Immunology and Microbiology | 7 | 16% |
Agricultural and Biological Sciences | 6 | 14% |
Business, Management and Accounting | 1 | 2% |
Other | 3 | 7% |
Unknown | 10 | 23% |