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Ahmed, S. et al.

Salahuddin Ahmed, Matthew D. Silverman, Hubert Marotte, Kevin Kwan, Natalie Matuszczak, Alisa E. Koch,

Down-regulation of myeloid cell leukemia 1 by epigallocatechin-3-gallate sensitizes rheumatoid arthritis synovial fibroblasts to tumor necrosis factor alpha-induced apoptosis.

OBJECTIVE: Overexpression of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) in rheumatoid arthritis (RA) synovial fibroblasts is a major cause of their resistance to tumor necrosis factor alpha (TNFalpha)-induced apoptosis. This study was undertaken to evaluate the efficacy of epigallocatechin-3-gallate (EGCG) in down-regulating Mcl-1 expression and its mechanism of RA synovial fibroblast sensitization to TNFalpha-induced apoptosis. METHODS: EGCG effects on cultured RA synovial fibroblast cell morphology, proliferation, and viability over 72 hours were determined by microscopy and a fluorescent cell enumeration assay. Caspase 3 activity was determined by a colorimetric assay. Western blotting was used to evaluate the apoptosis mediators poly(ADP-ribose) polymerase (PARP), Mcl-1, Bcl-2, Akt, and nuclear translocation of NF-kappaB. RESULTS: In RA synovial fibroblasts, EGCG (5-50 microM) inhibited constitutive and TNFalpha-induced Mcl-1 protein expression in a concentration- and time-dependent manner (P<0.05). Importantly, EGCG specifically abrogated Mcl-1 expression in RA synovial fibroblasts and affected Mcl-1 expression to a lesser extent in osteoarthritis and normal synovial fibroblasts or endothelial cells. Inhibition of Mcl-1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts, which was mediated via down-regulation of the TNFalpha-induced Akt and NF-kappaB pathways. Caspase 3 activation by EGCG also suppressed RA synovial fibroblast growth, and this effect was mimicked by Akt and NF-kappaB inhibitors. Interestingly, Mcl-1 degradation by EGCG sensitized RA synovial fibroblasts to TNFalpha-induced PARP cleavage and apoptotic cell death. CONCLUSION: Our findings indicate that EGCG itself induces apoptosis and further sensitizes RA synovial fibroblasts to TNFalpha-induced apoptosis by specifically blocking Mcl-1 expression and, hence, may be of promising adjunct therapeutic value in regulating the invasive growth of synovial fibroblasts in RA.[1]

References

Down-regulation of myeloid cell leukemia 1 by epigallocatechin-3-gallate sensitizes rheumatoid arthritis synovial fibroblasts to tumor necrosis factor alpha-induced apoptosis. Ahmed, S., Silverman, M.D., Marotte, H., Kwan, K., Matuszczak, N., Koch, A.E. Arthritis Rheum. (2009) [Pubmed]

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