ABSTRACT
Rheumatoid arthritis (RA) is a systemic autoimmune disorder mainly characterized by inflammation of the synovial tissue that can lead to destruction of bone and cartilage. Sinomenine is an alkaloid extracted from the stem of the Chinese medicinal plant Sinomenium acutum. It has been reported that sinomenine has immunosuppressive and anti-inflammatory properties. However, the molecular mechanism underlying the effect of sinominine on IL-1ß-induced human RA fibroblast-like synoviocytes (RAFLS) is poorly understood. Therefore, in this study, we investigated the effect of sinomenine on the expression of inflammatory cytokines in IL-1ß-treated human RAFLS in vitro and the underlying mechanism. RAFLS viability was evaluated using the MTS assay after sinomenine treatment. The levels of inflammatory cytokines were measured with ELISA, RT-PCR and western blot, respectively. The levels of TLR4 and its downstream signaling targets were determined by western blot analysis. We found that sinomenine suppressed not only NO and PGE2 production but also iNOS and COX-2 expression in IL-1ß-induced RAFLS. It also inhibited the expression of TNF-α and IL-6 in IL-1ß-stimulated RAFLS. Furthermore, sinomenine prevented IL-1ß-induced TLR4, MyD88 and p-NF-κB p65 expression. Taken together, these results demonstrated that sinomenine prevented IL-1ß-induced inflammation in human RAFLS at least in part by inhibiting the TLR4/MyD88/NF-κB signaling pathway, suggesting that sinomenine could be a potential agent in the treatment of RA.
Subject(s)
Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Morphinans/pharmacology , Synoviocytes/drug effects , Antirheumatic Agents/isolation & purification , Arthritis, Rheumatoid/pathology , Blotting, Western , Cell Survival/drug effects , Cells, Cultured , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression Regulation/drug effects , Humans , Inflammation/drug therapy , Inflammation/pathology , Morphinans/isolation & purification , Myeloid Differentiation Factor 88/metabolism , NF-kappa B/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Sinomenium/chemistry , Synoviocytes/metabolism , Toll-Like Receptor 4/metabolismABSTRACT
Sinomenine (SIN) is the active principle of the Chinese medical plant Sinomenium acutum which is widely used for the treatment of rheumatoid arthritis (RA) in China. Recently, several groups indicated that myeloid differentiation primary response protein 88 (MyD88) might be associated with disease progression of RA. Here, we observed the effect of SIN on MyD88 expression and showed its therapeutic role in RA. First, immunohistochemical staining in clinical specimens showed that MyD88 was mainly located in characteristic pathological structures of RA synovial tissues. Second, we found that MyD88 was overexpressed in the synovial tissues of the rats with adjuvant-induced arthritis (AIA). Treatment with SIN markedly decreased the expression of MyD88 in AIA rats. Finally, we provided evidences that SIN suppressed inflammation response and inflammation-induced joint destructive progression and arthritis symptoms in AIA rats. Therefore, SIN is an effective therapeutic agent for RA. Targeting MyD88 signaling may provide new methods for the treatment of RA.
