A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway.

摘要: In rheumatoid arthritis(RA) pathogenesis, activated RA fibroblast-like synoviocytes (RA-FLSs) exhibit similar proliferative features as tumor cells and subsequent erosion to cartilage will eventually lead joint destruction. Therefore, it is imperative search for compounds, which can effectively inhibit the abnormal activation of RA-FLSs, retard progression.3'3-Diindolylmethane (DIM), major product acid-catalyzed oligomerization indole-3-carbinol from cruciferous vegetables, has been reported be functionally relevant inhibition migration, invasion carcinogenesis in some solid tumors. this study, we explored anti-proliferation, anti-metastasis anti-inflammation effects DIM on RA-FLSs well underlying molecular mechanisms. To do this, primary were isolated patients an animal model. Cell proliferation, migration measured using CCK-8, scratch, Transwell assays, respectively. The Matrix metalloproteinases (MMPs) inflammatory factors mRNA key molecules such those involved aberrantly-activated signaling pathway response necrosis factor α(TNF-α), a typical characteristic mediator RA-FLS, quantitatively by real-time PCR western blotting. Moreover, effect adjuvant induced arthritis(AIA) models was evaluated with C57BL/6 mice vivo. results showed that inhibited RA-FLS vitro. Meanwhile, dramatically suppressed TNF-α-induced increases levels MMP-2, MMP-3, MMP-8, MMP-9; proinflammatory IL-6, IL-8, IL-1β. Mechanistic studies revealed able suppress phosphorylated not only p38, JNK MAPK but AKT, mTOR downstream AKT/mTOR pathway. treatment decreased expression cytokines serum alleviated arthritis severity knee joints AIA mice. Taken together, our findings demonstrate could reduce TNF-α vitro blocking prevent inflammation destruction vivo, suggests might have therapeutic potential RA.