Pyrrolidine dithiocarbamate, a NF-kappa B inhibitor, upregulates MMP-1 and MMP-13 in IL-1 beta-stimulated rheumatoid arthritis fibroblast-like synoviocytes

Abstract

Activated NF-kappa B plays an important role in the expression of matrix metalloproteinase (MMP)-1 and MMP-13 in rheumatoid arthritis and osteoarthritis. The objective of this study was to determine the effects of the NF-kappa B inhibitor pyrrolidine dithiocarbamate (PDTC) on the expression of MMPs in IL-1 beta-stimulatecl fibroblast-like synoviocytes (FLSs) of rheumatoid arthritis patients. FLSs were treated with IL-1 beta (10 ng/ml) for 24 h in the presence or absence of PDTC. The level of MMP-1 and MMP-13 increased in response to PDTC in time- and dose-dependent manners in IL-1 beta-stimulated FLSs; the expressions of IL-6 and vascular endothelial growth factor (VEGF) decreased in a PDTC concentration-dependent manner. However, PDTC-mediated repression of IL-6 and VEGF expression was not observed in TNF-alpha-stimulated rheumatoid arthritis FLSs. In contrast, other NF-kappa B inhibitors, such as fenofibrate, N-acetylcysteine and MG132, decreased MMP expression in IL-1 beta-stimulated FLSs. The stimulatory effect of PDTC on MMP expression was not mimicked by specific inhibitors of the mitogen-activated protein kinase (MAPK) signaling pathway. Treatments with 100 mu M PDTC did not inhibit the phosphorylation of p-ERK1/2, p-P38, and p-JNK, or the transnuclear migration of NF-kappa B through degradation Of I kappa B-alpha in IL-1 beta-stimuiated FLSs. These results suggest that the increase of MMP expression may occur in a stimuli-specific manner or by an NF-kappa B independent mechanism. Therefore, therapeutic NF-kappa B inhibitors should be thoroughly studied before their clinical use in treating rheumatoid arthritis, as undesirable genes may be upregulated through unknown mechanisms, possibly resulting in worse symptoms. (C) 2009 Published by Elsevier B.V.