Among epigenetic
enzymes,
histone deacetylases (HDACs) are responsible for regulating the expression of an extensive array of genes by reversible deacetylation of nuclear
histones as well as a large number of non-
histone proteins. Initially proposed for
cancer therapy, recently the interest for
HDAC inhibitors (HDACi) as orally active, safe, and
anti-inflammatory agents is rising due to their ability in reducing the severity of inflammatory and
autoimmune diseases. In particular, selective HDAC3, HDAC6, and HDAC8 inhibitors have been described to downregulate the expression of pro-inflammatory
cytokines (TNF-α, TGF-β, IL-1β, and IL-6). Herein, using KB31, C2C12, and 3T3-J2 cell lines, we demonstrated that, under
lipopolysaccharide-induced in vitro
inflammation, HDAC3/6/8 inhibitor
MC2625 and HDAC6-selective inhibitor MC2780 were effective at a concentration of 30 ng/mL to downregulate
mRNA expression of pro-inflammatory
cytokines (IL-1β and IL-6) and to promote the transcription of
IL-10 gene, without affecting the cell viability. Afterwards, we investigated by immunohistochemistry the activity of
MC2625 and MC2780 at a concentration of 60 ng/kg animal weight to regulate
silicone-triggered immune response in C57BL/6J female mice. Our findings evidenced the ability of such inhibitors to reduce host
inflammation in
silicone implants promoting a thickness reduction of peri-implant fibrous
capsule, upregulating
IL-10 expression, and reducing the production of both IL-1β and
IL-6. These results underline the potential application of
MC2625 and MC2780 in
inflammation-related diseases.