Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes.
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.
Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4946, USA.
Salahuddin
S
Ahmed
Naizhen
N
Wang
Mathew
M
Lalonde
Victor M
VM
Goldberg
Tariq M
TM
Haqqi
D000975:Antioxidants / Q000494:pharmacology; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D016328:NF-kappa B / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D059808:Polyphenols; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013662:Tea / Q000737:chemistry; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000975:Antioxidants; D005419:Flavonoids; D007375:Interleukin-1; D016328:NF-kappa B; D010636:Phenols; D059808:Polyphenols; D012333:RNA, Messenger; D013662:Tea; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; D002392:Catechin; C045651:epigallocatechin gallate; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1