TNFa: Promotes Thl7 Cell Differentiation through IL-6 and IL-1 beta Produced by Monocytes in Rheumatoid Arthritis

摘要

TNFa plays an important role in autoimmune pathogenesis and is the main therapeutic target of rheumatoid arthritis. However, its underlying mechanism is not completely understood. In this study, we described that Thl7 cells were accumulated in synovial fluid, which was attributable to TNFa aberrantly produced in rheumatoid synovium. Interestingly, TNFa cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1 beta and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFa was shown to enhance the phosphorylation level of STAT3 and the expression level of transcription factor RORC of CD4+ T cells when cultured with CD14+ monocytes. Treatment with an approved TNFa blocking antibody showed marked reduction in the levels of IL-6, IL-1 beta, and IL-17 and the expression level of STAT3 phosphorylation in relation to Thl7 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNFa in the pathogenic Thl7 cell differentiation in rheumatoid arthritis.