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

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.

• Authors: Jung Won Lee, Soung-Min Lee, Jaeyoung Chun, Jong Pil Im, Su-Kil Seo, Nina Ha, Young Il Choi, Joo Sung Kim
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 26 Issue 6 Pg. 852-862 (05 12 2020) ISSN: 1536-4844 [Electronic] England
• PMID: 31895948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Cytokines
• Lipopolysaccharides
• NF-kappa B
• Dextran Sulfate
• Histone Deacetylase 6

Topics

• Animals
• Colitis (drug therapy)
• Cytokines (metabolism)
• Dextran Sulfate
• Disease Models, Animal
• Epithelial Cells (drug effects)
• Female
• Histone Deacetylase 6 (antagonists & inhibitors, pharmacology)
• Humans
• Intestinal Mucosa (pathology)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (drug effects)
• RAW 264.7 Cells
• Signal Transduction (drug effects)