Inhibition of KDM4A activity as a strategy to suppress interleukin-6 production and attenuate colitis induction.

Abstract

4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) functions as a hapten and fluoresces upon binding to proteins. Therefore, fluorescence visualization of hapten-proteins is a feature of the colitis induced by NBD-Cl. Using this colitis model, we located activated fibroblasts in the vicinity of hapten-proteins upon colitis induction and observed interleukin (IL)-6 production in the activated fibroblasts. We screened herbal ingredients using primary fibroblasts stimulated with tumor necrosis factor α (TNF-α) and found the suppressive action of Atractylodin on IL-6 production. Under TNF-α stimulation, Atractylodin induced the tri-methylation of histone H3 at lysine residue 9, which impaired the binding between NF-κB and the IL-6 promoter on the genomic DNA. Atractylodin inhibited KDM4A but not KDM6A activity. Atractylodin administration attenuated colitis induction. The KDM4A inhibitor ML324 showed similar actions on IL-6 production and colitis induction. We propose the inhibition of KDM4A activity as a strategy to suppress IL-6 production and attenuate colitis induction.

• Authors: Kazuhiro Ishiguro, Osamu Watanabe, Masanao Nakamura, Takeshi Yamamura, Masanobu Matsushita, Hidemi Goto, Yoshiki Hirooka
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 180 Pg. 120-127 (07 2017) ISSN: 1521-7035 [Electronic] United States
• PMID: 28511912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• 4-chloro-7--nitrobenzo-2-oxa-1,3-diazole
• Azoles
• Furans
• Interleukin-6
• Nitro Compounds
• Plant Preparations
• Tumor Necrosis Factor-alpha
• interleukin-6, mouse
• atractylodin
• Trinitrobenzenesulfonic Acid
• Histone Demethylases
• JMJD2A protein, mouse

Topics

• Animals
• Azoles
• Cells, Cultured
• Colitis (chemically induced, drug therapy, pathology)
• Colon (drug effects, pathology)
• Female
• Fibroblasts (drug effects, metabolism)
• Furans (pharmacology, therapeutic use)
• Histone Demethylases (antagonists & inhibitors, metabolism)
• Interleukin-6 (antagonists & inhibitors, genetics)
• Mice, Inbred BALB C
• Nitro Compounds
• Plant Preparations (pharmacology, therapeutic use)
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha (pharmacology)