Aristolochic acid downregulates monocytic matrix metalloproteinase-9 by inhibiting nuclear factor-κB activation

Chih Jen Wu, Yung Chen Chou, Yu Wen Cheng, Che Jen Hsiao, Chen Hsu Wang, Hsin Yu Wang, Joen Rong Sheu, George Hsiao

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Aristolochic acid (AA)-associated nephropathy was described as being characterized by a rapid progressive enhancement of interstitial renal fibrosis. Renal tissue fibrosis occurs because of an imbalance of extracellular matrix (ECM) accumulation and matrix metalloproteinase (MMP) activation. Much evidence indicates that inflammatory renal disease including monocyte and mesangial interactions is linked to the development and progression of renal remodeling. In this study, we found that AA showed concentration-dependent inhibition of tumor necrosis factor (TNF)-α-induced MMP-9 activation with an IC 50 value of 6.4 ± 0.5 μM in human monocytic THP-1 cells. A similar effect was also noted with different ratios of AAs (types I and II). However, AA had no inhibitory effect on the intact enzymatic activity of MMP-9 at a concentration of 20 μM. On the other hand, the level of tissue inhibitor of metalloproteinase (TIMP)-1 was not induced by AA, but it suppressed TNF-α-induced MMP-9 protein and messenger RNA expressions. AA also significantly inhibited TNF-α-induced IκBα degradation. Furthermore, an electrophoretic mobility shift assay and a reported gene study, respectively, revealed that AA inhibited TNF-α-induced NF-κB translocation and activation. In addition, compared to other NF-κB inhibitors, AA exerted significant inhibition of MMP-9 activation and monocyte chemotactic protein-1-directed invasion. From these results, we concluded that AA, a natural compound, inhibits TNF-α-induced MMP-9 in human monocytic cells possibly through the NF-κB signal pathway. These results also imply that AA may be involved in alteration of matrix homeostasis during renal fibrosis in vivo.

Original languageEnglish
Pages (from-to)209-219
Number of pages11
JournalChemico-Biological Interactions
Volume192
Issue number3
DOIs
Publication statusPublished - Jul 15 2011

Keywords

  • Aristolochic acid
  • Matrix metalloproteinase-9
  • Monocytes
  • NF-κB
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Toxicology

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