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Int. J. Mol. Sci. 2017, 18(7), 1394; 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

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
4
Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
5
School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
6
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
7
Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 110, Taiwan
8
Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 26 May 2017 / Revised: 19 June 2017 / Accepted: 26 June 2017 / Published: 29 June 2017
(This article belongs to the Special Issue Sepsis)
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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. View Full-Text
Keywords: histone deacetylase; matrix metalloproteinases-9 (MMP-9); lipopolysaccharide (LPS); endotoxemia histone deacetylase; matrix metalloproteinases-9 (MMP-9); lipopolysaccharide (LPS); endotoxemia
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MDPI and ACS Style

Jan, J.-S.; Chou, Y.-C.; Cheng, Y.-W.; Chen, C.-K.; Huang, W.-J.; Hsiao, G. The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo. Int. J. Mol. Sci. 2017, 18, 1394.

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