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Research ArticleDrug Discovery and Translational Medicine

An HDAC6 Inhibitor Confers Protection and Selectively Inhibits B-Cell Infiltration in DSS-Induced Colitis in Mice

Anh Do, Robert C. Reid, Rink-Jan Lohman, Matthew J. Sweet, David P. Fairlie and Abishek Iyer
Journal of Pharmacology and Experimental Therapeutics January 2017, 360 (1) 140-151; DOI: https://doi.org/10.1124/jpet.116.236711
Anh Do
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia
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Robert C. Reid
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia
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Rink-Jan Lohman
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia
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Matthew J. Sweet
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia
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David P. Fairlie
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia
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Abishek Iyer
Institute for Molecular Bioscience (IMB), IMB Centre for Inflammation and Disease Research, and Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland, Australia
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Abstract

Small molecule histone deacetylase (HDAC) inhibitors with anti-inflammatory activity may be candidates for targeting intestinal inflammatory pathways in inflammatory bowel disease (IBD). This study investigated whether treatment with a potent HDAC6 inhibitor, BML-281, could protect against colonic inflammation and prevent inflammatory cell infiltration into the colon to drive disease pathology in a mouse model of acute dextran sodium sulfate (DSS) colitis. Control and acute DSS-colitis mice were treated with BML-281 (1 mg/kg per day s.c. and 10 mg/kg per day s.c.) for 8 days. Changes in disease pathology, colonic structure, function, alterations in inflammatory milieu, together with colonic inflammatory cell flux, were assessed by weight loss and disease activity index in vivo and by flow cytometry, gene expression, and histology ex vivo. Anti-inflammatory responses of BML-281 on human polymorphonuclear leukocytes were assessed in vitro. Administration of BML-281 to DSS-treated mice attenuated colitis, weight loss, and disease pathology, including changes in colon structure and function, by eliciting broad-spectrum anti-inflammatory effects and preventing infiltration and activation of key immune cells in the lamina propria of the intestinal epithelium. Among different immune cells, BML-281 particularly suppressed the infiltration of CD19+ B-cells into the inflamed colonic lamina propria. This study supports the targeting of HDAC6 as an anti-inflammatory strategy for treating colon inflammation progressing to IBD. Some HDAC inhibitors are used in the clinic to treat cancer, and the results here for BML-281 highlight the potential for HDAC6 inhibitors to be used in a clinical setting for preventing and treating colonic inflammation and IBD in humans.

Footnotes

    • Received July 20, 2016.
    • Accepted November 7, 2016.
  • The authors thank the National Health and Medical Research Council of Australia for a Senior Principal Research Fellowship to D.F. (1027369), a Senior Research Fellowship to M.J.S. (1107915), and grant funding (1047921, 1030169, 1074016); the Australian Research Council for funding of a Centre of Excellence in Advanced Molecular Imaging (CE140100011); and the University of Queensland for a PhD scholarship to A.D., a UQ Postdoctoral Research Fellowship to A.I. and UQ early career grant funding to A.I. and R.J.L.

  • dx.doi.org/10.1124/jpet.116.236711.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 360 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 360, Issue 1
1 Jan 2017
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Research ArticleDrug Discovery and Translational Medicine

HDAC6 Inhibitor in DSS Colitis Mice

Anh Do, Robert C. Reid, Rink-Jan Lohman, Matthew J. Sweet, David P. Fairlie and Abishek Iyer
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 140-151; DOI: https://doi.org/10.1124/jpet.116.236711

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Research ArticleDrug Discovery and Translational Medicine

HDAC6 Inhibitor in DSS Colitis Mice

Anh Do, Robert C. Reid, Rink-Jan Lohman, Matthew J. Sweet, David P. Fairlie and Abishek Iyer
Journal of Pharmacology and Experimental Therapeutics January 1, 2017, 360 (1) 140-151; DOI: https://doi.org/10.1124/jpet.116.236711
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