The novel HDAC8 inhibitor WK2-16 attenuates lipopolysaccharide-activated matrix metalloproteinase-9 expression in human monocytic cells and improves hypercytokinemia in vivo

Jing Shiun Jan, Yung Chen Chou, Yu Wen Cheng, Chih Kuang Chen, Wei Jan Huang, George Hsiao

研究成果: 雜誌貢獻文章同行評審

10 引文 斯高帕斯(Scopus)

摘要

Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP-1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-κB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis.
原文英語
文章編號1394
期刊International Journal of Molecular Sciences
18
發行號7
DOIs
出版狀態已發佈 - 七月 1 2017

Keywords

  • Endotoxemia
  • Histone deacetylase
  • Lipopolysaccharide (LPS)
  • Matrix metalloproteinases-9 (MMP-9)

ASJC Scopus subject areas

  • 催化
  • 分子生物學
  • 電腦科學應用
  • 光譜
  • 物理與理論化學
  • 有機化學
  • 無機化學

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