Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model.
10.3858/emm.2008.40.5.574
- Author:
Yongseok CHOI
1
;
Song Kyu PARK
;
Hwan Mook KIM
;
Jong Soon KANG
;
Yeo Dae YOON
;
Sang Bae HAN
;
Jeung Whan HAN
;
Jee Sun YANG
;
Gyoonhee HAN
Author Information
1. School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
anti-inflammatory agents;
histone deacetylases;
NF-kappaB;
nitric oxide;
transcription factor AP-1;
tumor necrosis factor-alpha;
vorinostat
- MeSH:
Animals;
Blotting, Western;
Cell Line;
Cell Survival/drug effects;
Cytokines/blood/genetics/*metabolism;
Electrophoretic Mobility Shift Assay;
Endotoxemia/blood/metabolism/pathology;
Enzyme Inhibitors/chemistry/*pharmacology;
Histone Deacetylases/*antagonists & inhibitors;
Hydroxamic Acids/chemistry/*pharmacology;
Interleukin-1beta/genetics/metabolism;
Interleukin-6/genetics/metabolism;
Macrophages/cytology/*drug effects/metabolism;
Mice;
Mitogen-Activated Protein Kinase 1/metabolism;
Mitogen-Activated Protein Kinase 3/metabolism;
Mitogen-Activated Protein Kinases/metabolism;
Molecular Structure;
NF-kappa B/metabolism;
Nitric Oxide/metabolism;
Nitric Oxide Synthase Type II/genetics/metabolism;
Phosphorylation/drug effects;
Piperidones/chemistry/*pharmacology;
Protein Binding/drug effects;
Reverse Transcriptase Polymerase Chain Reaction;
Transcription Factor AP-1/metabolism;
Tumor Necrosis Factor-alpha/blood/genetics/metabolism
- From:Experimental & Molecular Medicine
2008;40(5):574-581
- CountryRepublic of Korea
- Language:English
-
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-alpha, a proinflammatory cytokine, and nitric oxide (NO), a proinflammatory effector molecule, in LPS-stimulated RAW264.7 cells and peritoneal macrophages. It also inhibited TNF-alpha production in vivo as demonstrated in a LPS-induced mouse endotoxemia model. The levels of TNF-alpha, IL-1beta, 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-kappaB, a transcription factor, to a specific DNA sequence showed that the binding of NF-kappaB 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.
