title: Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis.
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.
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: Rink-Jan
authors.initials: RJ
authors.lastname: Lohman
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: Abishek
authors.initials: A
authors.lastname: Iyer
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.); d.fairlie@imb.uq.edu.au.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fairlie
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: Adam
authors.initials: A
authors.lastname: Cotterell
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: Praveer
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: David A
authors.initials: DA
authors.lastname: Vesey
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.);
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.affiliation: Centre for Inflammation and Disease Research, The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia (R.J.L., A.I., T.J.F., A.C., P.G., R.C.R., M.J.S., D.P.F.); Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland, Department of Medicine at the Princes Alexandra Hospital, Australia (D.A.V.); d.fairlie@imb.uq.edu.au.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D056572:Histone Deacetylase Inhibitors; D018836:Inflammation Mediators