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Novel Histone Deacetylase 6 Inhibitor CKD-506 Inhibits NF-κB Signaling in Intestinal Epithelial Cells and Macrophages and Ameliorates Acute and Chronic Murine Colitis

Authors
 Jung Won Lee  ;  Soung-Min Lee  ;  Jaeyoung Chun  ;  Jong Pil Im  ;  Su-Kil Seo  ;  Nina Ha  ;  Young Il Choi  ;  Joo Sung Kim 
Citation
 INFLAMMATORY BOWEL DISEASES, Vol.26(6) : 852-862, 2020-05 
Journal Title
 INFLAMMATORY BOWEL DISEASES 
ISSN
 1078-0998 
Issue Date
2020-05
Keywords
histone deacetylase 6 inhibitor ; NF-κB ; acute colitis ; chronic colitis ; inflammatory bowel diseases
Abstract
Background: Selective blocking of HDAC6 has become a promising strategy in treating inflammatory bowel disease. CKD-506 is a novel isoform-selective inhibitor of histone deacetylase 6. The present study was performed to evaluate the effect of CKD-506 on the NF-κB signaling pathway in intestinal epithelial cells (IECs) and macrophages and on murine models of acute and chronic colitis. Methods: RAW264RAW264.7 murine macrophages and COLO 205 human IECs were pretreated with CKD-506 and then stimulated with lipopolysaccharides (LPS). Cytokine expression of TNF-α, interleukin (IL)-6, IL-8, and IL-10 was measured by ELISA. The effect of CKD-506 on NF-κB signaling was evaluated by Western blotting of IκBα phosphorylation/degradation and electrophoretic mobility shift assay. In vivo studies were performed using a dextran sulfate sodium (DSS)-induced acute colitis model, a chronic colitis model in IL-10 knockout mice, and an adoptive transfer model. Colitis was quantified by the disease activity index, colon length, and histopathologic evaluation. Results: CKD-506 suppressed the expression of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α in IECs and macrophages. CKD-506 strongly inhibited IκBα phosphorylation/degradation and the DNA-binding activity of NF-κB. Oral administration of CKD-506 attenuated DSS-induced acute colitis and chronic colitis in IL-10-/- and adoptive transfer models. CKD-506 ameliorated weight loss, disease activity, and histopathologic score in colitis mice and downregulated IκBα phosphorylation and pro-inflammatory cytokine production significantly. Conclusions: CKD-506 blocked NF-κB signaling in IECs and macrophages and ameliorated experimental acute and chronic murine colitis models, which suggests that CKD-506 is a promising candidate for inflammatory bowel disease treatment as a small molecular medicine.
Full Text
https://academic.oup.com/ibdjournal/article/26/6/852/5694342
DOI
10.1093/ibd/izz317
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Chun, Jaeyoung(천재영) ORCID logo https://orcid.org/0000-0002-4212-0380
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/180016
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