Green Tea Polyphenol Epigallocatechin-3-gallate (EGCG) Differentially Inhibits Interleukin-1β-Induced Expression of Matrix Metalloproteinase-1 and -13 in Human Chondrocytes

Abstract

Interleukin-1␤ (IL-1␤)-induced inflammatory response in arthritic joints include the enhanced expression and activity of matrix metalloproteinases (MMPs), and their matrix degrading activity contribute to the irreversible loss of cartilage and may also be associated with sustained chronic inflammation. We have earlier shown that green tea (Camellia sinensis) polyphenol epigallocatechin-3-gallate (EGCG) was non-toxic to human chondrocytes [Singh R, Ahmed S, Islam N, Goldberg VM, and Haqqi TM ( Here we show that EGCG at micromolar concentrations was highly effective in inhibiting the IL-1␤-induced glycosaminoglycan (GAG) release from human cartilage explants in vitro. EGCG also inhibited the IL-1␤-induced mRNA and protein expression of MMP-1 and MMP-13 in human chondrocytes. Importantly, EGCG showed a differential, dose-dependent inhibitory effect on the expression and activity of MMP-13 and MMP-1. A similar differential dose-dependent inhibition of transcription factors NF-B and AP-1 by EGCG was also noted. These results for the first time demonstrate a differential dosedependent effect of EGCG on the expression and activity of MMPs and on the activities of transcription factors NF-B and AP-1 and provide insights into the molecular basis of the reported anti-inflammatory effects of EGCG. These results also suggest that EGCG or compounds derived from it may be therapeutically effective inhibitors of IL-

Inhibition of pectin methyl esterase activity by green tea catechins

“…Our result showing PME inhibition by PP60, or green tea catechins, is consistent with previous work showing that green tea extract is a potent inhibitor of activity or expression of a variety of enzymes in vitro and in vivo (Ahmed et al, 2004;Aucamp et al, 1997;Morre et al, 2003;Okello et al, 2004;Persson et al, 2006;Vankemmelbeke et al, 2003;Zhang and Rock, 2004), including esterases (Okello et al, 2004). The enzyme-inhibiting and -inducing activities of green tea are mainly attributed to the polyphenolic flavonoids found in PP60: (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), and (-)-gallocatechin gallate (GCG), and while individual catechins may have differential effects, there may also be synergistic effects among catechins (e.g., Morre et al, 2003).…”

“…The enzyme-inhibiting and -inducing activities of green tea are mainly attributed to the polyphenolic flavonoids found in PP60: (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG), and (-)-gallocatechin gallate (GCG), and while individual catechins may have differential effects, there may also be synergistic effects among catechins (e.g., Morre et al, 2003). These catechins can inhibit enzymes by direct competitive interactions (Persson et al, 2006;Vankemmelbeke et al, 2003), by altering regulation of expression at the genetic level (Ahmed et al, 2004), or both.…”

“…The gallate-containing catechins, EGCG in particular, have been implicated in inhibition of FabG and FabI reductases (Zhang and Rock, 2004), carboxypeptidases such as angiotensin-converting enzyme (Persson et al, 2006), as well as nitric oxide synthase (Singh et al, 2002), oxidases (Aucamp et al, 1997;Morre et al, 2003) and matrix-degrading metalloproteinases, or MMPs (Ahmed et al, 2004;Demeule et al, 2000;Vankemmelbeke et al, 2003) in in vitro systems.…”

Luteolin downregulates IL-1β-induced MMP-9 and -13 expressions in osteoblasts via inhibition of ERK signalling pathway

“…MMPs expression is upregulated in response to various bone-resorptive stimuli 2,6 . The proinflammatory cytokines such as interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), produced in inflammatory condition such as arthritis joint by activated synovial cells and infiltrating macrophages, are considered to be one of the most potent catabolic factors in bone 7 . These cytokines induce the enhanced production of MMPs by osteoblasts, which can cause irreversible matrix degradation and subsequent joint destruction.…”

Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production

“…EGCG has recently attracted attention for its emerging antiarthritic and immunemodulating properties (15)(16)(17). Our previous studies on EGCG defined the mechanisms of its inhibitory potential against the mediators of inflammation and cartilage degradation in human chondrocytes (16,18,19).…”