TNF alpha Promotes Th17 Cell Differentiation through IL-6 and IL-1 beta Produced by Monocytes in Rheumatoid Arthritis

TNF alpha 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 Th17 cells were accumulated in synovial fluid, which was attributable to TNF alpha aberrantly produced in rheumatoid synovium. Interestingly, TNF alpha 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. TNF alpha 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 TNF alpha 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 Th17 cell differentiation in patients with rheumatoid arthritis. The study provides new evidence supporting the critical role of TNF alpha in the pathogenic Th17 cell differentiation in rheumatoid arthritis.