TY - JOUR
T1 - Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model
AU - Choi, Yongseok
AU - Park, Song Kyu
AU - Hwan, Mook Kim
AU - Jong, Soon Kang
AU - Yeo, Dae Yoon
AU - Sang, Bae Han
AU - Jeung, Whan Han
AU - Jee, Sun Yang
AU - Han, Gyoonhee
PY - 2008/10
Y1 - 2008/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=57349114027&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57349114027&partnerID=8YFLogxK
U2 - 10.3858/emm.2008.40.5.574
DO - 10.3858/emm.2008.40.5.574
M3 - Article
C2 - 18985016
AN - SCOPUS:57349114027
VL - 40
SP - 574
EP - 581
JO - Experimental and Molecular Medicine
JF - Experimental and Molecular Medicine
SN - 1226-3613
IS - 5
ER -