Differential anti-inflammatory activity of HDAC inhibitors in human macrophages and rat arthritis

Lohman, Rink-Jan, Iyer, Abishek, Fairlie, Thomas J., Cotterell, Adam, Gupta, Praveer, Reid, Robert C., Vesey, David A., Sweet, Matthew J. and Fairlie, David P. (2016) Differential anti-inflammatory activity of HDAC inhibitors in human macrophages and rat arthritis. Journal of Pharmacology and Experimental Therapeutics, 356 2: 387-396. doi:10.1124/jpet.115.229328

Author Lohman, Rink-Jan
Iyer, Abishek
Fairlie, Thomas J.
Cotterell, Adam
Gupta, Praveer
Reid, Robert C.
Vesey, David A.
Sweet, Matthew J.
Fairlie, David P.
Title Differential anti-inflammatory activity of HDAC inhibitors in human macrophages and rat arthritis
Journal name Journal of Pharmacology and Experimental Therapeutics   Check publisher's open access policy
ISSN 0022-3565
Publication date 2016-02
Sub-type Article (original research)
DOI 10.1124/jpet.115.229328
Open Access Status Not Open Access
Volume 356
Issue 2
Start page 387
End page 396
Total pages 10
Place of publication Bethesda, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2017
Language eng
Formatted abstract
Vorinostat and other inhibitors of different histone deacetylase (HDAC) enzymes are currently being sought to modulate a variety of human conditions, including chronic inflammatory diseases. Some HDAC inhibitors are anti-inflammatory in rodent models of arthritis and colitis, usually at cytotoxic doses that may cause side effects. Here, we investigate the dose-dependent pro- and anti-inflammatory efficacy of two known inhibitors of multiple HDACs, vorinostat and BML281, in human macrophages and in a rat model of collagen-induced arthritis by monitoring effects on disease progression, histopathology, and immunohistochemistry. Both HDAC inhibitors differentially modulated lipopolysaccharide (LPS)-induced cytokine release from human macrophages, suppressing release of some inflammatory mediators (IL12p40, IL6) at low concentrations (<3 µM) but amplifying production of others (TNF, IL1β) at higher concentration (>3 μΜ). This trend translated in vivo to rat arthritis, with anti-inflammatory activity inversely correlating with dose. Both compounds were efficacious only at a low dose (1 mg⋅kg−1⋅day−1 s.c.), whereas a higher dose (5 mg⋅kg−1⋅day−1 s.c.) showed no positive effects on reducing pathology, even showing signs of exacerbating disease. These striking effects suggest a smaller therapeutic window than previously reported for HDAC inhibition in experimental arthritis. The findings support new investigations into repurposing HDAC inhibitors for anti-inflammatory therapeutic applications. However, HDAC inhibitors should be reinvestigated at lower, rather than higher, doses for enhanced efficacy in chronic diseases that require long-term treatment, with careful management of efficacy and long-term safety.
Keyword Histone deacetylase inhibitors
Collagen-induced arthritis
Inflammatory responses
Mediated activation
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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