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 mM) but amplifying production of others (TNF, IL1b) at higher concentration (.3 mΜ). 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 21 ×day 21 s.c.), whereas a higher dose (5 mg×kg 2 1 ×day 2 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.

Impact of the microbial derived short chain fatty acid propionate on host susceptibility to bacterial and fungal infections in vivo

“…LPS vs E. coli , and Pam 3 CSK 4 vs S. aureus ). Notably, and in line with recent reports4647, propionate at 4 mM increased E. coli -induced IL-1β secretion by BMDMs (Fig. 1D).…”

“…Similar disparities have been observed with other SCFAs2940454654. BMDCs were more resistant to propionate than BMDMs, human monocytes and whole blood.…”

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…Treatment with MPT0G009 at 25 mg/kg resulted in similar effects to that seen with vorinostat at 200 mg/kg. A more recent study showed that panHDACi, including vorinostat, are quite toxic above 10 µM concentrations in cells and even at a 10 mg/kg dose in rodents with collagen-induced arthritis, but were tolerated and optimally antiinflammatory at a lower in vivo dose of 1 mg/kg [25]. This suggests that the higher doses mentioned above should not be considered safe and efficacious, especially in already immune-compromised individuals suffering arthritis.…”

“…(targets HDAC 1), BML-275 (targets HDAC 6) have been found to have anti-arthritic activity in rodent models at much lower doses (1-25 mg/kg/day) [7,25]. For instance, in a collagen-induced arthritis (CIA) model, prophylactic treatment with MS-275 (3 and 10mg/kg/day s.c.) demonstrated significant anti-resorptive effects on the bone [7].…”

“…Importantly, HDACi can be used at lower, non-cytotoxic, doses to treat non-malignant disease than is required to treat malignancy [25]. However, they need to be used long-term for the treatment of chronic inflammatory diseases and residual or cumulative toxicity may have contributed to their lack of progression to the clinic.…”