An HDAC6 inhibitor confers protection and selectively inhibits B-cell infiltration in DSS-induced colitis in mice

Do, Anh, Reid, Robert C., Lohman, Rink-Jan, Sweet, Matthew J., Fairlie, David P. and Iyer, Abishek (2017) An HDAC6 inhibitor confers protection and selectively inhibits B-cell infiltration in DSS-induced colitis in mice. The Journal of Pharmacology and Experimental Therapeutics, 360 1: 140-151. doi:10.1124/jpet.116.236711


Author Do, Anh
Reid, Robert C.
Lohman, Rink-Jan
Sweet, Matthew J.
Fairlie, David P.
Iyer, Abishek
Title An HDAC6 inhibitor confers protection and selectively inhibits B-cell infiltration in DSS-induced colitis in mice
Journal name The Journal of Pharmacology and Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
1521-0081
Publication date 2017-01-01
Year available 2016
Sub-type Article (original research)
DOI 10.1124/jpet.116.236711
Open Access Status Not yet assessed
Volume 360
Issue 1
Start page 140
End page 151
Total pages 12
Place of publication Bethesda, MD United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Language eng
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 DSS-colitis. Control and acute DSS-colitis mice were treated with BML-281 (1mg/kg/day s.c. & 10mg/kg/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 polymorphonucleocytes 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 highlights the potential for HDAC6 inhibitors to be evaluated in a clinical setting for preventing and treating colonic inflammation and IBD in humans.
Keyword Acetylation
Colitis
Inflammation
Inflammatory
Bowel disease (IBD)
Lymphocytes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Tue, 06 Dec 2016, 00:35:05 EST by Susan Allen on behalf of Institute for Molecular Bioscience