Journal
CLINICAL AND EXPERIMENTAL RHEUMATOLOGY
Volume 39, Issue 2, Pages 289-303Publisher
CLINICAL & EXPER RHEUMATOLOGY
Keywords
iguratimod; rheumatoid arthritis; microRNA-146a; rheumatoid arthritis-fibroblast-like synoviocytes; collagen-induced arthritis rat
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This study demonstrates that iguratimod can ameliorate the progression of rheumatoid arthritis by regulating miR-146a-mediated IRAK1 expression and TRAF6/JNK1 pathway. The experimental results indicate that iguratimod can reduce cell proliferation, migration, invasion, and inflammatory cytokine expression in RA-FLS, while enhancing apoptosis.
Objective This study aimed to evaluate the therapeutic effect of iguratimod and its regulatory role on microRNA (miR-146a) and the downstream genes in treating rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS) and collagen-induced arthritis (CIA) rat model. Methods RA-FLS was isolated from knee synovial tissue of an active RA patient. In vitro, the effect of miR-146a mimic/inhibition on RA-FLS functions was investigated. Then the effect of Iguratimod on cell viability, proliferation, apoptosis, migration, invasion, inflammatory cytokines, miR-146a and its downstream gene/pathway in RA-FLS was evaluated. In vivo, the collagen induced arthritis (CIA) rat model was constructed, then the effects of iguratimod, miR-146a inhibition and their combination on treating CIA rat were assessed. Results Iguratimod treatment increased miR-146a while decreased cell proliferation, IRAK1 and TRAF6/JNK1 pathway in RA-FLS in a dose-dependent manner. Notably, iguratimod treatment repressed cell proliferation, migration, invasion, TNF-alpha, IL-1 beta, IL-6, IL-17, IRAK1 and TRAF6/JNK1 pathway in RA-FLS, while miR-146a inhibition alleviated the abovementioned effects of Iguratimod on RA-FLS. The in vivo experiments disclosed that iguratimod reduced systemic arthritis score, and decreased TNF-alpha, IL-1 beta, IL-6, IL-17, IRAK1 as well as TRAF6/JNK1 pathway, while enhanced apoptosis in synovial tissue of CIA rat model; and in miR-146a inhibition treated CIA rat model, the effect of iguratimod was diminished. Conclusion Iguratimod ameliorates RA progression via regulating miR-146a mediated IRAK1 expression and TRAF6/JNK1 pathway.
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