Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1β-induced expression of matrix metalloproteinase-1 and-13 in human chondrocytes
Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1β-induced expression of matrix metalloproteinase-1 and-13 in human chondrocytes
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DOI：
10.1124/jpet.103.059220
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发表时间：
2004-02-01
影响因子：
3.5
通讯作者：
Haqqi, TM
中科院分区：
文献类型：
--
作者：
Ahmed, S;Wang, NZ;Haqqi, TM
白细胞介素-1 β (il -1 β)诱导的关节炎关节炎症反应包括基质金属蛋白酶（MMPs）的表达和活性增强，其基质降解活性导致软骨的不可逆损失，也可能与持续的慢性炎症有关。我们早前已经证明绿茶（Camellia sinensis）多酚表没食子儿茶素-3-没食子酸酯（EGCG）对人软骨细胞无毒[Singh R， Ahmed S, Islam N, Goldberg VM, and Haqqi TM (2002) Arthritis Rheum 46: 2079-2086]并抑制关节炎关节炎症介质的表达[Haqqi TM， Anthony DD, Gupta S, Ahmed N, Lee MS, Kumar GK, and Mukhtar H (1999) pronatalacadsci USA 96: 4524-4529]。本研究表明，微摩尔浓度的EGCG在体外抑制il -1诱导的人软骨外植体的糖胺聚糖（GAG）释放方面非常有效。EGCG还能抑制il -1诱导的人软骨细胞中MMP-1和MMP-13 mRNA和蛋白的表达。重要的是，EGCG对MMP-13和MMP-1的表达和活性表现出不同的剂量依赖性抑制作用。EGCG对转录因子NF-kappaB和AP-1也有类似的差异剂量依赖性抑制作用。这些结果首次证明了EGCG对MMPs的表达和活性以及转录因子NF-kappaB和AP-1活性的差异剂量依赖性作用，并为EGCG报道的抗炎作用的分子基础提供了见解。这些结果还表明，EGCG或其衍生的化合物可能是关节炎中il -1 β诱导的基质降解酶产生的有效抑制剂。
Interleukin-1beta (IL-1beta)-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 (2002) Arthritis Rheum 46: 2079-2086] and inhibits the expression of inflammatory mediators in arthritic joints [Haqqi TM, Anthony DD, Gupta S, Ahmed N, Lee MS, Kumar GK, and Mukhtar H (1999) Proc Natl Acad Sci USA 96: 4524-4529]. Here we show that EGCG at micromolar concentrations was highly effective in inhibiting the IL-1beta-induced glycosaminoglycan (GAG) release from human cartilage explants in vitro. EGCG also inhibited the IL-1beta-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-kappaB and AP-1 by EGCG was also noted. These results for the first time demonstrate a differential dose-dependent effect of EGCG on the expression and activity of MMPs and on the activities of transcription factors NF-kappaB 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-1beta-induced production of matrix-degrading enzymes in arthritis.