Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model

Yongseok Choi, Song Kyu Park, Mook Kim Hwan, Soon Kang Jong, Dae Yoon Yeo, Bae Han Sang, Whan Han Jeung, Sun Yang Jee, Gyoonhee Han

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

In light of the anti-inflammatory properties of histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), we examined a new HDAC inhibitor KBH-A42 for its anti-inflammatory activities. KBH-A42 showed noteworthy anti-inflammatory properties in vitro via suppression of the production of TNF-α, a proinflammatory cytokine, and nitric oxide (NO), a proinflammatory effector molecule, in LPS-stimulated RAW264.7 cells and peritoneal macrophages. It also inhibited TNF-α production in vivo as demonstrated in a LPS-induced mouse endotoxemia model. The levels of TNF-α, IL-1β, IL-6 and iNOS mRNAs determined by RT-PCR propose that the inhibition of these pro-inflammatory mediators by KBH-A42 resulted from inhibiting expression of these genes. However, the EMSA study to see the effect of KBH-A42 on the binding of NF-κB, a transcription factor, to a specific DNA sequence showed that the binding of NF-κB to DNA was not changed regardless of increasing the concentration of KBH-A42 in the presence and absence of LPS stimulation. Interestingly, DNA binding of another transcription factor AP-1 dose-dependently increased by KBH-A42. KBH-A42 differentially regulated the phosphorylation of MAP kinases. While the phosphprylation of ERK1/2 and SAPK/JNK was not affected by KBH-A42, the phosphorylation of p38 decreased by KBH-A42. These results showed that KBH-A42 inhibits production of proinflammatory cytokines in macrophages by decreasing their mRNA levels, and p38 kinase is involved in the KBH-A42-mediated inhibition.

Original languageEnglish
Pages (from-to)574-581
Number of pages8
JournalExperimental and Molecular Medicine
Volume40
Issue number5
DOIs
Publication statusPublished - 2008 Oct

Keywords

  • Anti-inflammatory agents
  • Histone deacetylases
  • NF-κ B
  • Nitric oxide
  • Transcription factor AP-1
  • Tumor necrosis factor-α
  • Vorinostat

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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