Study on association of DNA promoter methylation patterns with antioxidant response and tissue remodeling in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA), a multifactorial disease, involving various immune cells and pathways including Polymorphonuclear Neutrophils (PMNs) and Peripheral Blood Mononuclear Cells (PBMCs). The tendency of PMNs to generate oxidative stress, regulate anti-oxidant responses, modulate inflammatory processes, subsequently contributes towards joint damage. Present study observed an imbalance in the oxidative milieu and elevated inflammatory mediators (IL-1and#946;, IL-6 and TNF-and#945;) in isolated PMNs, PBMCs and sera of RA patients compared to healthy controls. DNA methylation gene regulation studies revealed a hypermethylated CpG island on promoter region of MMP9 gene and correlated with several parameters of RA disease. The expression of proteins involved in oxidative pathway (Keap1 and Nrf2), tissue degradation (MMP2 and MMP9) and DNA methylation (Dnmt1) were reduced in RA patients when compared to controls. Correlational studies of disease severity, oxidant/anti-oxidant parameters, intracellular expression of proteins, inflammatory parameters, and DNA methylation studies revealed an intricate and complex interplay of several mechanisms involved in RA progression. Current study opens up new research areas in involvement of neutrophils and underlying mechanisms in RA that can be targeted in future for their prognostic, diagnostic, and therapeutic purposes. newline