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).
MeSH terms
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Acetylation
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Animals
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Cell Cycle Proteins / metabolism
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Cell Survival / drug effects
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Chondroitin Sulfate Proteoglycans / metabolism
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Chromosomal Proteins, Non-Histone / metabolism
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Cyclooxygenase 2 / drug effects
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Cytokines / drug effects*
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Cytokines / metabolism*
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Down-Regulation
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Endotoxemia
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Histone Deacetylase 1 / drug effects
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / drug effects*
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Histone Deacetylases / metabolism*
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Humans
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Interleukin-6
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JNK Mitogen-Activated Protein Kinases / drug effects
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Lipopolysaccharides / pharmacology*
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MAP Kinase Signaling System / drug effects
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Male
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Matrix Metalloproteinase 9 / drug effects*
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Inbred C57BL
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Monocytes / metabolism
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NF-kappa B / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / drug effects
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Repressor Proteins / drug effects*
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Repressor Proteins / metabolism*
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Sepsis / drug therapy
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Signal Transduction / drug effects
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THP-1 Cells / drug effects
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Tubulin / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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YY1 Transcription Factor / metabolism
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p38 Mitogen-Activated Protein Kinases / drug effects
Substances
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Cell Cycle Proteins
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Chondroitin Sulfate Proteoglycans
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Chromosomal Proteins, Non-Histone
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Cytokines
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Histone Deacetylase Inhibitors
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IL6 protein, human
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Interleukin-6
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Lipopolysaccharides
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NF-kappa B
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RNA, Messenger
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Repressor Proteins
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SMC3 protein, human
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Tubulin
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Tumor Necrosis Factor-alpha
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YY1 Transcription Factor
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Cyclooxygenase 2
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Matrix Metalloproteinase 9
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HDAC1 protein, human
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HDAC8 protein, human
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Histone Deacetylase 1
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Histone Deacetylases