50 Citations (Scopus)

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-κB (NF-κB), 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)-α stimulated expression of MMP-9 in a human monocytic cell line, THP-1. Our results show that TNF-α-induced expression of MMP-9 at both mRNA and protein levels was completely blocked by EK5 in a concentration-dependent (1-20 μM) manner. We also found that EK5 markedly suppressed NF-κB signaling as detected by the NF-κB reporter gene assay but had no effects on the degradation of IκBα or translocation of NF-κB. 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-κB 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.

Original languageEnglish
Pages (from-to)403-412
Number of pages10
JournalChemico-Biological Interactions
Volume184
Issue number3
DOIs
Publication statusPublished - Mar 2010

Fingerprint

Matrix Metalloproteinase 9
Tumor Necrosis Factor-alpha
Genes
Inflammation
Phosphorylation
Chromatin Immunoprecipitation
Pathologic Processes
Matrix Metalloproteinases
Reporter Genes
Chromatin
Extracellular Matrix
Tumors
Assays
Anti-Inflammatory Agents
Transcription Factors
Down-Regulation
Cells
N-2-(4-bromophenyl) ethyl caffeamide
Association reactions
Cytokines

Keywords

  • MMP-9
  • Monocyte
  • NF-κB
  • TNF-α

ASJC Scopus subject areas

  • Toxicology

Cite this

Nuclear-targeted inhibition of NF-κB on MMP-9 production by N-2-(4-bromophenyl) ethyl caffeamide in human monocytic cells. / Chou, Yung Chen; Sheu, Joen Rong; Chung, Chi Li; Chen, Chung Yung; Lin, Fan Li; Hsu, Ming Jen; Kuo, Yueh Hsiung; Hsiao, George.

In: Chemico-Biological Interactions, Vol. 184, No. 3, 03.2010, p. 403-412.

Research output: Contribution to journalArticle

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T1 - Nuclear-targeted inhibition of NF-κB on MMP-9 production by N-2-(4-bromophenyl) ethyl caffeamide in human monocytic cells

AU - Chou, Yung Chen

AU - Sheu, Joen Rong

AU - Chung, Chi Li

AU - Chen, Chung Yung

AU - Lin, Fan Li

AU - Hsu, Ming Jen

AU - Kuo, Yueh Hsiung

AU - Hsiao, George

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N2 - 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-κB (NF-κB), 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)-α stimulated expression of MMP-9 in a human monocytic cell line, THP-1. Our results show that TNF-α-induced expression of MMP-9 at both mRNA and protein levels was completely blocked by EK5 in a concentration-dependent (1-20 μM) manner. We also found that EK5 markedly suppressed NF-κB signaling as detected by the NF-κB reporter gene assay but had no effects on the degradation of IκBα or translocation of NF-κB. 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-κB 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.

AB - 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-κB (NF-κB), 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)-α stimulated expression of MMP-9 in a human monocytic cell line, THP-1. Our results show that TNF-α-induced expression of MMP-9 at both mRNA and protein levels was completely blocked by EK5 in a concentration-dependent (1-20 μM) manner. We also found that EK5 markedly suppressed NF-κB signaling as detected by the NF-κB reporter gene assay but had no effects on the degradation of IκBα or translocation of NF-κB. 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-κB 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.

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