title: Nuclear-targeted inhibition of NF-kappaB on MMP-9 production by N-2-(4-bromophenyl) ethyl caffeamide in human monocytic cells.
abstract: Aberrant remodeling of the extracellular matrix occurs in many pathological processes, and its breakdown is mainly accomplished by matrix metalloproteinases (MMPs), which participate in the course of inflammation and tumor invasion. Nuclear factor-kappaB (NF-kappaB), a key transcription factor for the production of MMP-9, can be activated by various proinflammatory cytokines and promotes inflammation. In the present study, we investigated the intracellular mechanism for the inhibitory effects of an analogue of N-hydroxycinnamoylphenalkylamides, N-2-(4-bromophenyl) ethyl caffeamide (EK5), on tumor necrosis factor (TNF)-alpha stimulated expression of MMP-9 in a human monocytic cell line, THP-1. Our results show that TNF-alpha-induced expression of MMP-9 at both mRNA and protein levels was completely blocked by EK5 in a concentration-dependent (1-20microM) manner. We also found that EK5 markedly suppressed NF-kappaB signaling as detected by the NF-kappaB reporter gene assay but had no effects on the degradation of IkappaBalpha or translocation of NF-kappaB. Interestingly, chromatin immunoprecipitation results revealed that the association between p65 and MMP-9 promoter gene was completely abrogated by EK5, but the p65 phosphorylation was not affected. Overall, our findings suggest that EK5 inhibits MMP-9 production through the nuclear-targeted down-regulation of NF-kappaB signaling in human monocytic cells and this may provide a novel molecular basis of EK5 activity. Further studies are needed to verify its anti-inflammatory effects.
authors.affiliation: Graduate Institute of Medical Sciences and Department of Pharmacology, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110-31, Taiwan.
authors.forename: Yung-Chen
authors.initials: YC
authors.lastname: Chou
authors.forename: Joen-Rong
authors.initials: JR
authors.lastname: Sheu
authors.forename: Chi-Li
authors.initials: CL
authors.lastname: Chung
authors.forename: Chung-Yung
authors.initials: CY
authors.lastname: Chen
authors.forename: Fan-Li
authors.initials: FL
authors.lastname: Lin
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Hsu
authors.forename: Yueh-Hsiung
authors.initials: YH
authors.lastname: Kuo
authors.forename: George
authors.initials: G
authors.lastname: Hsiao
mesh_terms: D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; C549043:N-2-(4-bromophenyl) ethyl caffeamide; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9