Cordycepin inhibits IL-1β-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts
1Department of Biochemistry, Institute for Medical Science, 2Department of Microbiology and Immunology, Chonbuk National University Medical School, Jeonju, 3Department of Physiology, School of Oriental Medicine, Wonkwang University, Chonbuk, 4Department of Internal Medicine, Chonbuk National University Hospital, Jeonju, 5Department of Pharmacy, College of Pharmacy, Ewha Womans University, Seoul and 6Department of Surgery, Chonbuk National University Hospital, Jeonju, South Korea.
Correspondence to: Y.-R. Lee, Department of Biochemistry, Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-180, South Korea. E-mail: mindyr{at}chonbuk.ac.kr
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Abstract |
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Objective. MMP is a key enzyme in the degradation of extracellular matrices, and its expression plays important roles in inflammatory diseases. Cordycepin (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological activities, such as anti-cancer, anti-inflammatory and anti-infection activities. In this study, we aimed at the inhibitory effect of cordycepin on IL-1β-induced MMP-1 and MMP-3 expression as well as the molecular basis using RA synovial fibroblasts (RASFs).
Methods. RASFs were isolated from synovial tissue obtained from 12 patients with RA and cultured in monolayer. Expression of MMP-1 and MMP-3 was evaluated using western blotting and real-time PCR. Chemokines were analysed by ELISA. The phosphorylation of mitogen-activated protein kinase was measured by western blotting. Electrophoretic mobility shift assay was performed to evaluate binding activities of DNA to nuclear factor-
B (NF-B) and activator protein-1 (AP-1).
Results. Cordycepin inhibited IL-1β-induced MMP-1 and MMP-3 expressions in RASFs in a dose-dependent manner. Among various chemokines [such as monocyte chemoattractant protein-1 (MCP-1), GRO-
, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) and epithelial neutrophil activating peptide 78 (ENA-78)], cordycepin specifically blocked IL-1β-induced ENA-78 production in RASF. Moreover, cordycepin significantly inhibited IL-1β-induced p38/JNK and AP-1 activation, but not extracellular signal-regulated kinase (ERK) and NF-B activation.
Conclusions. Cordycepin is a potent inhibitor of IL-1β-induced chemokine production and MMP expression and strongly blocks the p38/JNK/AP-1 signalling pathway in RASFs.
KEY WORDS: Cordycepin, Interleukin-1β, Matrix metalloproteinase, p38 mitogen-activated protein kinase, Activator protein-1
E.-M. Noh and J.-S. Kim equally contributed to this work.
Submitted 6 May 2008;
revised version accepted 29 September 2008.
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