title: 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-inducedin vitroinflammation, 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 ofIL-10gene, 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.
authors.affiliation: Dipartimento Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Liddo
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Valente
authors.affiliation: Dipartimento Organi di Senso, Sapienza Università di Roma, Roma, Italy.
authors.forename: Samanta
authors.initials: S
authors.lastname: Taurone
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, Italy.
authors.forename: Clemens
authors.initials: C
authors.lastname: Zwergel
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, Italy.
authors.forename: Biagina
authors.initials: B
authors.lastname: Marrocco
authors.affiliation: Dipartimento Organi di Senso, Sapienza Università di Roma, Roma, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Turchetta
authors.affiliation: Dipartimento Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Conconi
authors.affiliation: Dipartimento di Neuroscienze, Clinica di Chirurgia Plastica, Università di Padova, Padova, Italy, and.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Scarpa
authors.affiliation: Dipartimento Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertalot
authors.affiliation: Dipartimento Scienze del Farmaco, Università di Padova, Padova, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schrenk
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Roma, Italy.|Istituto Pasteur - Fondazione Cenci Bolognetti, Sapienza Università di Roma, Roma, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Dipartimento Organi di Senso, Sapienza Università di Roma, Roma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Artico
keywords: Breast silicone implants; HDAC inhibitors; epigenetics; inflammation; pro-inflammatory cytokines