Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis.
J Pharmacol Exp Ther
; 356(2): 387-96, 2016 Feb.
Article
en En
| MEDLINE
| ID: mdl-26660228
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, IL1ß) 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 mgâ
kg(-1)â
day(-1) s.c.), whereas a higher dose (5 mgâ
kg(-1)â
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Artritis Experimental
/
Mediadores de Inflamación
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Inhibidores de Histona Desacetilasas
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Macrófagos
/
Antiinflamatorios
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
J Pharmacol Exp Ther
Año:
2016
Tipo del documento:
Article