PT  - JOURNAL ARTICLE
AU  - Rink-Jan Lohman
AU  - Abishek Iyer
AU  - Thomas J. Fairlie
AU  - Adam Cotterell
AU  - Praveer Gupta
AU  - Robert C. Reid
AU  - David A. Vesey
AU  - Matthew J. Sweet
AU  - David P. Fairlie
TI  - Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis
AID  - 10.1124/jpet.115.229328
DP  - 2016 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 387--396
VI  - 356
IP  - 2
4099  - http://jpet.aspetjournals.org/content/356/2/387.short
4100  - http://jpet.aspetjournals.org/content/356/2/387.full
SO  - J Pharmacol Exp Ther2016 Feb 01; 356
AB  - 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.