Histone deacetylase inhibitors restore IL-10 expression in lipopolysaccharide-induced cell inflammation and reduce IL-1β and IL-6 production in breast silicone implant in C57BL/6J wild-type murine model

Abstract

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.

Keywords:

• Breast silicone implants
• epigenetics
• HDAC inhibitors
• inflammation
• pro-inflammatory cytokines

Acknowledgements

The authors thank Garland R. Marshall, Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, for critical reading of the manuscript and scientific discussion, and Carola Cenzi, Department of Pharmaceutical and Pharmacological Sciences, Padova University, Italy, for technical support.

Declaration of interest

This work was supported by Italian Ministry of Health (RF-2010-2318330 Grant), IIT-Sapienza Project grant, and FP7 Projects BLUEPRINT/282510 and A-PARADDISE/602080 for A.M., and by Sapienza Ateneo Project 2013 and Nobile S.p.a. for M.A.

Supplementary material available online

Supplementary Table S1