Effects of Treatment with the Hypomethylating Agent 5-aza-2'-deoxycytidine in Murine Type II Collagen-Induced Arthritis.

Maria Cristina Petralia,Emanuela Mazzon,Katia Mangano,Marco Cutuli,Ferdinando Nicoletti,Paolo Fagone,Fabiola Scandurra,Maria Sofia Basile,Roberto Di Marco,Andrea Saraceno

doi:10.3390/ph12040174

Abstract

The emerging role of epigenetics in the pathogenesis of autoimmune diseases has recently attracted much interest on the possible use of epigenetic modulators for the prevention and treatment of these diseases. In particular, we and others have shown that drugs that inhibit DNA methylation, such as azacitidine (AZA) and decitabine (DAC), already used for the treatment of acute myeloid leukemia, exert powerful beneficial effects in rodent models of type 1 diabetes, multiple sclerosis, and Guillain Barrè syndrome. Along this line of research, we have presently studied the effects of DAC in a murine model of rheumatoid arthritis induced by type II collagen and have demonstrated that DAC administration was associated with a significant amelioration of the clinical condition, along with in vivo and ex vivo modification of the immunological profile of the so-treated mice, that exhibited a diminished production of Th1 and Th17 pro-inflammatory cytokines and reduction of anti-type II collagen autoantibodies.

Highlights

Rheumatoid arthritis (RA) is an immunoinflammatory disease, probably of autoimmune origin, that is primarily characterized by chronic inflammation of the joints [1]
The histological hallmark of RA consists of symmetric synovial proliferation, cartilage destruction and bone damage that appears to be driven by the synergic action of autoreactive T cells and B cells, that produce pro-inflammatory cytokines and autoantibodies capable of amplifying the vicious circuit of cartilage destruction and inducing synovial hyperplasia [2]
Macrophages can be subdivided into pro-inflammatory M1 and anti-inflammatory M2 macrophages, that are characterized by the production of the pro-inflammatory cytokines TNF-alpha, IL-6, IL-12, IL-18, and IL-23, and of the anti-inflammatory cytokine IL-10, respectively [9,10]

Summary

Introduction

Rheumatoid arthritis (RA) is an immunoinflammatory disease, probably of autoimmune origin, that is primarily characterized by chronic inflammation of the joints [1]. Macrophages can be subdivided into pro-inflammatory M1 and anti-inflammatory M2 macrophages, that are characterized by the production of the pro-inflammatory cytokines TNF-alpha, IL-6, IL-12, IL-18, and IL-23, and of the anti-inflammatory cytokine IL-10, respectively [9,10]. Both preclinical and clinical evidence coming from rodent models of RA and RA patients indicate that the CD4+T cell belonging to the Th1 and Th17 subsets, along with M1 macrophages, play a key role in the development and maintenance of RA, as opposed to anti-inflammatory Th2 and Th3 cells, and M2 macrophages that seem to play a protective role on the course of the disease [11]

Methods

Results

Conclusion