Abstract
BackgroundRheumatoid arthritis is a progressive and systemic autoimmune disease seriously compromises human health. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Shikonin has anti-inflammatory and immunomodulatory activities. But, its role on synovitis of rheumatoid arthritis is unknown.MethodsThe DBA/1 male mice were randomly divided into the following three groups (n = 6): (1) the normal control group of mice, (2) the CIA (collagen-induced arthritis) group in which mice suffered from arthritis induced by collagen, (3) the SKN (shikonin) group of mice which got arthritis and given intragastrically with shikonin 4 mg/kg per day continuously for 20 days,(4) the MTX (methotrexate) group of mice which got arthritis and orally administration with shikonin 0.5 mg/kg once two days continuously for 20 days. The therapeutic effect of shikonin on collagen induced arthritis mice was tested by arthritis incidence rate, arthritis score and inflammatory joint histopathology. The invasion, adhesion and migration of fibroblast like synoviocytes induced by tumor necrosis factor-α were applied to measure the anti-synovitis role of shikonin. The effect of shikonin on expression of interleukin-6, interleukin-1β and tumor necrosis factor-α was measured by enzyme linked immunosorbent assay. The interaction between shikonin and suppressor of cytokine signaling 1 was verified by molecular docking. The signaling pathways activated by shikonin were measured by western blot.ResultsShikonin decreased the arthritis score and arthritis incidence, and inhibited inflammation of inflamed joints in collagen induced arthritis mice. And shikonin reduced the number of vimentin+cells in collagen induced arthritis mice inflamed joints. Meanwhile, shikonin suppressed tumor necrosis factor-α-induced invasion, adhesion and migration of fibroblast like synoviocytes and reduced the expression of interleukin-6, interleukin-1β and tumor necrosis factor-α. And we found that shikonin targeted suppressor of cytokine signaling 1. More interestingly, shikonin blocked the phosphorylation of Janus kinase 1/signal transducer andactivator of transcription 1/signal transducer andactivator of transcription 6 in synovial tissues and in fibroblast like synoviocytes.ConclusionShikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis.
Highlights
Rheumatoid arthritis (RA) is a systemic, progressive and autoimmune disease, which characterized by chronic inflammatory synovial hyperplasia, hypertrophy and bone joint invasion, which seriously compromises human health [1,2,3]
Shikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis
Ltd.; DAPI was purchased from AAT Bioquest company; complete and incomplete Freund’s adjuvant (C/ IFA), bovine type II collagen were got from Chondrex; mouse interleukin -6 (IL-6), mouse tumor necrosis factor-α (TNF-α) and mouse IL-1β Enzyme‐linked immunosorbant assay (ELISA) kits from ABclonal; phosphorylated (p)-STAT6 antibody and p-JAK1 antibody were purchased from LifeSpan Biological Sciences and Cell Signaling Technology respectively; JAK1 antibody, anti-STAT6, anti-STAT1, p-STAT1 antibody, anti-GAPDH and anti-Vimentin antibodies were got from Abcam; TNF-α, IL-1β and IL-6 antibody were got from Abclonal; RiboFECTTM CP Transfection Kit were from RIOBIO; All real-time quantitative Polymerase Chain Reaction (PCR) reagents were purchased from OMEGA
Summary
Rheumatoid arthritis (RA) is a systemic, progressive and autoimmune disease, which characterized by chronic inflammatory synovial hyperplasia, hypertrophy and bone joint invasion, which seriously compromises human health [1,2,3]. Suppressor of cytokine signaling (SOCS) plays an important role in the immune system, which is a class of protein transduction molecules [5]. Janus kinase/signal transducer andactivator of transcription (JAK/STAT) is involved in the regulation of a variety of pathophysiological processes including cell proliferation, immune regulation, and inflammatory response, which is an important multifunctional cytokine transduction pathway [7]. SOCS1 is a negative regulator of JAK/STAT, which plays an important role in inflammation, autoimmune diseases and other diseases [9]. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Its role on synovitis of rheumatoid arthritis is unknown
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