Inhibition of TGF-β Signaling Suppresses Th17 Differentiation and Promotes Treg Numbers but does not Reduces Experimental Arthritis

ObjectivesTGF-β is an important growth factor to promote the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). The potential of TGF-β as therapeutic target in T cell-mediated diseases like rheumatoid arthritis (RA) is unclear. We investigated the effect of TGF-β inhibition on murine Th17 differentiation in vitro, on human RA synovial explants ex vivo, and on the development of experimental arthritis in vivo. MethodsMurine splenocytes were differentiated into Th17 cells, and the effect of the TGF-βRI inhibitor SB-505124 was studied. Synovial biopsies were cultured in the presence or absence of SB-505124. Experimental arthritis was induced in C57Bl6 mice and treated daily with SB-505124. FACS analysis was performed to measure different T cell subsets. Histological sections were analysed to determine joint inflammation and destruction.ResultsSB-505124 potently reduced murine Th17 differentiation by decreasing Il7a and Rorc gene expression and IL-17 protein production. SB-505124 significantly suppressed IL-6 production by synovial explants. In vivo, SB-505124 reduced Th17 levels, while increased levels of Tregs were observed. Despite this skewed Th17/Treg balance, SB-505124 treatment did not result in suppression of joint inflammation and destruction.ConclusionsBlocking TGF-β signalling suppresses Th17 differentiation and improves the Th17/Treg balance. However, SB-505124 treatment does not suppress experimental arthritis.

Inhibition of TGF-β Signaling Suppresses Th17 Differentiation and Promotes Treg Numbers but Does Not Reduce Experimental Arthritis.

ObjectivesTGF-β is an important growth factor to promote the differentiation of T helper 17 (Th17) as well as regulatory T cells (Treg). Due to its dual role, the potential of TGF-β as therapeutic target in T cell-mediated diseases like rheumatoid arthritis (RA) is unclear. In this study, we investigated the effect of TGF-β inhibition on murine Th17 differentiation in vitro, on human RA synovial explants ex vivo, and on the development of experimental arthritis in vivo. MethodsMurine splenocytes were differentiated into Th17 cells, and the effect of the TGF-βRI inhibitor SB-505124 on Th17 differentiation was studied. RA synovial biopsies were cultured for 24h in the presence or absence of SB-505124. Experimental arthritis models were induced in C57Bl6 mice, and were treated daily with SB-505124. FACS analysis was performed to measure different T cell subsets. Histological sections were analysed to determine joint inflammation and destruction.ResultsSB-505124 potently reduced murine Th17 differentiation by decreasing Il7a and Rorc gene expression and IL-17 protein production. SB-505124 significantly suppressed IL-6 production by RA synovial explants. In the Th17-driven arthritis model, SB-505124 reduced Th17 levels, while increased levels of Tregs were observed. Despite this skewed Th17/Treg balance, SB-505124 treatment did not result in suppression of joint inflammation and destruction in this model.ConclusionsBlocking TGF-β signalling suppresses Th17 differentiation and improves the Th17/Treg balance. However, SB-505124 treatment does not suppress experimental arthritis, and is therefore not an adequate way to target Th17-driven inflammation.

Inflammation in the Pathogenesis of Rheumatoid Arthritis and in Experimental Arthritis: Evaluation of Combinations of Carnosic Acid and Extract of Rhodiola rosea L. with Methotrexate

The host immune response generates the pro-inflammatory immune response as a protective measure against invading pathogens, allergens, and/or trauma. However, dysregulated and chronic inflammation may result in secondary damage to tissues and immune pathology to the host. Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease which primarily involves synovial inflammation, joint pain, immobility, and stiffness. Increased infiltration of inflammatory immune cells and fibroblast-like synoviocytes into joints, form pannus and small blood vessels that lead to synovium and cartilage destruction. In this chapter we will focus on the role of inflammatory cytokines (IL-1β, IL-6 and IL-17), chemokine monocyte chemotactic protein-1 and matrix metalloproteinase-9 in the pathogenesis of experimental arthritis in animals and in human RA. Further, we will be discussing about methotrexate’s (cornerstone of anti-rheumatic therapy) immune suppressing activity, anti-inflammatory properties of carnosic acid and extract of Rhodiola rosea L., and their innovative combination treatments with methotrexate in rat adjuvant arthritis.