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Int J Mol Sci. 2017 Jun 29;18(7). pii: E1394. doi: 10.3390/ijms18071394.

The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo.

Jan JS1,2, Chou YC3,4, Cheng YW5, Chen CK6,7,8, Huang WJ9, Hsiao G10,11,12.

Author information

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. d119101004@tmu.edu.tw.
2
Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. d119101004@tmu.edu.tw.
3
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. d102094011@tmu.edu.tw.
4
Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. d102094011@tmu.edu.tw.
5
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan. ywcheng@tmu.edu.tw.
6
Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan. d118105008@tmu.edu.tw.
7
School of Medicine, Chang Gung University, Taoyuan 333, Taiwan. d118105008@tmu.edu.tw.
8
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. d118105008@tmu.edu.tw.
9
Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 110, Taiwan. wjhuang@tmu.edu.tw.
10
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. geohsiao@tmu.edu.tw.
11
Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. geohsiao@tmu.edu.tw.
12
Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan. geohsiao@tmu.edu.tw.

Abstract

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.

KEYWORDS:

endotoxemia; histone deacetylase; lipopolysaccharide (LPS); matrix metalloproteinases-9 (MMP-9)

PMID:
28661460
PMCID:
PMC5535887
DOI:
10.3390/ijms18071394
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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