Gut Liver.  2023 Sep;17(5):766-776. 10.5009/gnl220159.

Novel Histone Deacetylase 6 Inhibitor Confers Anti-inflammatory Effects and Enhances Gut Barrier Function

• Lee JY
• Ma HW
• Kim JH
• Park IS
• Son M
• Ryu KH
• Shin J
• Kim SW
• Cheon JH

• KMID: 2546059
• DOI: http://doi.org/10.5009/gnl220159

Abstract

Background/Aims
The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 inhibitor, on human peripheral blood mononuclear cells (PBMCs) and CD4⁺ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function.
Methods
Lipopolysaccharide-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor (TNF)-α expression was measured using an enzyme-linked immunosorbent assay. The proliferation of CD4⁺ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, based on examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription polymerase chain reaction, immunofluorescence, and a fluorescein isothiocyanatedextran permeability assay.
Results
Secretion of TNF-α, a pivotal pro-inflammatory mediator in IBD, by lipopolysaccharidetriggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction in barrier permeability in a dose-dependent manner.
Conclusions
The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4 T cells and improves gut barrier function, suggesting its potential as a smallmolecule therapeutic option for IBD.

Keyword

HDAC6 inhibitor; Inflammatory bowel diseases; Barrier function; T-cell