TNFαPromotes Th17 Cell Differentiation through IL-6 and IL-1βProduced by Monocytes in Rheumatoid Arthritis

Abstract

TNFα 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 TNFα aberrantly produced in rheumatoid synovium. Interestingly, TNFα cannot induce IL-17 production of CD4+ T cells directly, but through the monocytes high levels of IL-1β and IL-6 in a TNFRI and TNFRII dependent manner from the active RA patients are produced. TNFα 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 TNFα blocking antibody showed marked reduction in the levels of IL-6, IL-1β, 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 TNFα in the pathogenic Th17 cell differentiation in rheumatoid arthritis.

The regenerating family member 3 β instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure

“…In line with our microarray data depicted in figure 3, the colon of Reg3b -deficient mice showed significant changes at the early stages of C. rodentium infection with respect to the expression level of the genes encoding for IL-22 and for tumour necrosis factor α (TNF-α) that indirectly functions as a Th17-inducing cytokine through IL-6 and IL-1β secretion by monocytes29 (figure 5A and data not shown). A significantly lowered protein level of TNF-α was confirmed among CD11c - CD11b + F4/80 + MHCII hi that were sorted from the intestine of Ripk2 -deficient mice when compared with controls (figure 5B).…”

Cucurbitacin E inhibits TNF-α-induced inflammatory cytokine production in human synoviocyte MH7A cells via suppression of PI3K/Akt/NF-κB pathways

“…TNF-α possesses a broad spectrum of pro-inflammatory properties in rheumatoid synovitis. It could induce the synthesis of pro-inflammatory cytokines (such as IL-1 and IL-6), chemokines (such as IL-8) and activates macrophages [14]. Previous studies showed that CuE reduced LPS-induced inflammation in mouse cell line RAW264.7 [12].…”

“…Cytokines concentrations correlated with clinical symptoms, inflammatory indicators, disease activity, and serum biomarkers during the RA therapy. The plasma levels of TNF-α, IL-6 IL-17A and IL-37, were found to be significantly increased in RA patients compared to healthy controls, and decreased in drug responders following DMARD treatment [14,29]. The proinflammatory productions IL-1β, IL-6 and IL-8 were measured after CuE treated to assess the anti-inflammatory outcome.…”

“…The release of cytokines, especially TNF-α, IL-1β, IL-6 and IL-8, causes synovial inflammation [14]. In this study, we investigated the effect and mechanism of CuE on TNF-α-induced inflammatory cytokines production in MH7A cells derived from RA-FLS [15].…”

Post-Traumatic Arthritis: The Role of Cytokine Levels in Serum and Synovial Fluid

“…Such neutralization of this cytokine or its receptors was shown to decrease arthritis symptoms in a rat model. IL-17 deficiency was also shown to protect the host against arthritis-related collagen damage in a rat model, and IL-17 gene therapy was shown to intensify it (van Baarsen et al, 2014;Zheng et al, 2014). It can be concluded, therefore, that IL-17 in RA patients might cause both inflammation and bone-destruction.…”