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

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-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. CKD-506 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(-/-) 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.