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KMID : 0620920080400050574
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Experimental & Molecular Medicine
2008 Volume.40 No. 5 p.574 ~ p.581
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Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model
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Choi Yong-seok
Han Sang-Bae
Kim Hwan-Mook
Kang Jong-Soon
Park Song-Kyu
Yoon Yeo-Dae
Han Jeung-Whan
Yang Jee-Sun
Han Gyoo-Hee
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Abstract
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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-a, a proinflammatory cytokine, and nitric oxide (NO), a proinflammatory effector molecule, in LPS-stimulated RAW264.7 cells and peritoneal macrophages. It also inhibited TNF-a production in vivo as demonstrated in a LPS-induced mouse endotoxemia model. The levels of TNF-a, IL-1b, 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-kB, a transcription factor, to a specific DNA sequence showed that the binding of NF-kB 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.
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KEYWORD
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anti-inflammatory agents, histone deacetylases, NF-κ B, nitric oxide, transcription factor AP-1, tumor necrosis factor-α , vorinostat
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