Epigallocatechin‐3‐gallate (EGCG) inhibits RANTES/CCL5 induced MMP‐1 and MMP‐13 expression in human rheumatoid arthritis synovial fibroblasts

Abstract

In rheumatoid arthritis (RA), activated synovial fibroblasts (FLS) produce chemokines to facilitate infiltration of inflammatory cells that result in inflammation and joint damage. RANTES/CCL5 is a potent chemokine shown to play an important role in RA pathogenesis, however, its role beyond chemotactic activity is not studied in RA. Using human RA‐FLS, we evaluated the effect of RANTES/CCL5 in inducing matrix metalloproteinase (MMP)‐1 and MMP‐13 activation. We also tested the efficacy of epigallocatechin‐3‐gallate (EGCG), a potent anti‐inflammatory compound, in regulating RANTES/CCL5‐induced MMP‐1 and MMP‐13 activation. Stimulation of RA‐FLS with RANTES/CCL5 (20‐100 ng/ml) caused in a dose‐dependent increase in MMP‐1 and MMP‐13 production (p<0.05' n=3). Quantitative RT‐PCR results showed that RANTES/CCL5 also increased MMP‐1 and MMP‐13 mRNA expression in RA‐FLS. Western blot analysis of the MAPK pathway showed that RANTES/CCL5 selectively phosphorylated JNK/SAPK, but not p38‐MAPK in RA‐FLS. Blocking of JNK pathway using a chemical inhibitor completely abrogated RANTES/CCL5‐induced MMP‐1 and MMP‐13 expression (p<0.05). RA‐FLS pretreatment with EGCG (2.5‐20 mM) dose‐dependently inhibited RANTES/CCL5‐induced MMP‐1 and MMP‐13 production (p<0.05 for 10 and 20 mM; n=4). Furthermore, EGCG selectively inhibited RANTES/CCL5‐induced phosphorylation of JNK p46‐isoform in a dose–dependent manner (p<0.05; n=4). Thus, EGCG may be of potential benefit in regulating RANTES/CCL5‐mediated inflammation and tissue destruction in RA.