The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo
| Autor: | Yu Wen Cheng, George Hsiao, Wei Jan Huang, Jing Shiun Jan, Yung Chen Chou, Chih Kuang Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine MAPK/ERK pathway Chromosomal Proteins Non-Histone THP-1 Cells Cell Cycle Proteins Histone Deacetylase 1 Matrix metalloproteinase p38 Mitogen-Activated Protein Kinases Monocytes Mice 0302 clinical medicine Tubulin THP1 cell line YY1 Transcription Factor Spectroscopy endotoxemia NF-kappa B Interleukin Acetylation histone deacetylase matrix metalloproteinases-9 (MMP-9) lipopolysaccharide (LPS) General Medicine Computer Science Applications Cell biology Matrix Metalloproteinase 9 030220 oncology & carcinogenesis Cytokines Tumor necrosis factor alpha Signal transduction Signal Transduction Cell Survival MAP Kinase Signaling System Down-Regulation Biology Histone Deacetylases Article Catalysis Inorganic Chemistry 03 medical and health sciences In vivo Sepsis Animals Humans RNA Messenger Physical and Theoretical Chemistry Molecular Biology Interleukin-6 Tumor Necrosis Factor-alpha Organic Chemistry JNK Mitogen-Activated Protein Kinases Molecular biology Histone Deacetylase Inhibitors Mice Inbred C57BL Repressor Proteins 030104 developmental biology Chondroitin Sulfate Proteoglycans Cyclooxygenase 2 TLR4 |
| Zdroj: | International Journal of Molecular Sciences; Volume 18; Issue 7; Pages: 1394 International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms18071394 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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