Regulation of Tumor Necrosis Factor-alpha Signaling in Rheumatoid Arthritis Synovial Fibroblasts by Green Tea Polyphenol Epigallocatechin-3-gallate

Rheumatoid arthritis (RA) is a chronic inflammatory disease, which affects about 1% of the population. It occurs when cytokines, such as interleukin (IL)-1β and tumor necrosis factor (TNF)-&agr;, stimulate synovial fibroblast proliferation leading to joint damage and destruction. Epigallocatechin-3-gallate (EGCG) is a polyphenol found in green tea that has been shown to have an anti-inflammatory effect in RA. Previous studies suggest that EGCG blocks IL-1β signaling pathways to inhibit angiogenesis and tissue destruction in RA. However, little research has been done to determine the effect of EGCG in the TNF-mediated pathways in RA synovial fibroblasts. In these experiments, we investigated the effects EGCG has on the TNF-&agr;-induced signal transduction pathways in RA synovial fibroblasts. In particular, we studied the effect of EGCG on the TNF receptors, TNF Receptor 1 (TNF-R1) and TNF Receptor 2 (TNF-R2), as well as downstream proteins, such as IL-6 and IL-8 in the TNF signaling pathways in RA synovial fibroblasts. We also compared the acute and chronic effects of EGCG on TNF-&agr;-mediated signaling pathways in RA synovial fibroblasts. Results of the study showed that EGCG modestly decreased TNF-R1 and increased TNF-R2 expression. Chronic low dose (100 nM - 1 &mgr;M) pretreatment of RA synovial fibroblasts resulted in a marked dose-dependent inhibition of TNF-&agr;-induced AKT activation. We also observed that EGCG modestly inhibited JNK and p38 with no effect on ERK MAPK in RA synovial fibroblasts. Inhibition of TNF-&agr;-induced downstream signaling pathways by EGCG resulted in decreases in IL-6 and IL-8 production by RA synovial fibroblasts. Overall, the results of this study suggest that EGCG decreases the inflammation and tissue invasion mediated by RA synovial fibroblast inflammatory cytokines via interfering with TNF-&agr; signaling.