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

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-[kappa]B signaling pathway in intestina...

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Published in:Inflammatory bowel diseases 2020-06, Vol.26 (6), p.852
Main Authors: Lee, Jung Won, Lee, Soung-Min, Chun, Jaeyoung, Im, Jong Pil, Seo, Su-Kil, Ha, Nina, Choi, Young il, Kim, Joo Sung
Format: Article
Language:English
Subjects:
Analysis
Colitis
Dextran
Enzyme-linked immunosorbent assay
Gastrointestinal diseases
Interleukins
Macrophages
Sulfates
Tumor necrosis factor
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Summary: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-[kappa]B 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-[alpha], interleukin (IL)-6, IL-8, and IL-10 was measured by ELISA. The effect of CKD-506 on NF-[kappa]B signaling was evaluated by Western blotting of I[kappa]B[alpha] 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-[alpha] in IECs and macrophages. CKD506 strongly inhibited I[kappa]B[alpha] phosphorylation/degradation and the DNA-binding activity of NF-[kappa]B. Oral administration of CKD-506 attenuated DSS-induced acute colitis and chronic colitis in [IL-10.sup.-/-] and adoptive transfer models. CKD-506 ameliorated weight loss, disease activity, and histopathologic score in colitis mice and downregulated I[kappa]B[alpha] phosphorylation and pro-inflammatory cytokine production significantly. Conclusions: CKD-506 blocked NF-[kappa]B 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. Key Words: histone deacetylase 6 inhibitor, NF-[kappa]B, inflammatory bowel diseases, acute colitis, chronic colitis
ISSN:1078-0998
DOI:10.1093/ibd/izz317