Green tea extract inhibits CXC chemokine production, but enhances CXC chemokine receptor expression in RA synovial fibroblasts

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which chemokines produced by the activated synovial fibroblasts promote joint destruction. In this study, we tested the efficacy of the polyphenol‐rich green tea extract (GTE) in regulating the CXC chemokine production and CXC chemokine receptor expression in RA synovial fibroblasts in vitro. The preincubation of RA synovial fibroblasts with GTE inhibited interleukin‐1β (IL‐1β 10 ng/ml)‐induced CXC chemokines growth regulated oncogene (GROα) and IL‐8 production in a dose‐dependent manner (IC50 values ~6.7 and ~16.5 μg/ml, respectively). However, the quantitative RT‐PCR analysis showed that GTE (10‐20 μg/ml) inhibits GROα, but enhances IL‐8, mRNA synthesis in RA synovial fibroblasts. Evaluation of the signaling pathways revealed that the PKCδ inhibitor, Rottlerin (10 μM), completely abrogated the IL‐1β‐induced RA synovial fibroblast GROα and IL‐8 production. We also found that GTE enhances the constitutive and IL‐1β‐induced expression of CXCR1 and CXCR2, the receptors utilized by GROα and IL‐8. To our surprise, a similar increase in the CXCR1/CXCR2 expression was mimicked by Rottlerin. Since RA synovial fibroblasts attract inflammatory cells by releasing chemokines, CXCR1/CXCR2 overexpression with reduced chemokine production by GTE may be a potential way of limiting the overall inflammation and joint destruction in RA.