The Production of Pro- And Antiinflammatory Cytokines by Synovial Fibroblasts of Patients With Rheumatoid Arthritis in Vitro When Using Dna Methylation Modulators - Investigative Study

The effects DNA methylation modulators on pro- and anti-inflammatory cytokine production by fibroblast-like synoviocytes (FLS) were evaluated using FLS obtained from synovial tissues of 8 patients with active RA and cultivated for 3-7 passages in vitro. It was shown that fenofibrate did not change levels of 5-methylcytosine (5-MeC) in FLS, genistein and ademetionine increased 5-MeC concentrations by 35%, and hydralazine resulted in twofold decrease of 5-MeC levels. There was a spontaneous production of IL-6, IL-17, IL- 18, and IL-10 by FLS cultures, an addition of IL-1β to cultures resulted in significant up-regulation of these cytokines synthesis. DNA methylation donors decreased IL-6 production by FLS. In contrast with hydralazine and genistein, ademetionine decreased IL-6 production by FLS. Synthesis of IL-17 was down-regulated with the addition of DNA-methylation modulators in low doses while there was no effect on IL-10 production. In conclusion, the effects of DNA-methylation modulators on production of pro- and anti-inflammatory cytokines by FLS is not only due to their impact on DNA methylation, but may be linked to other epigenetic mechanisms. FSC cultures may be used as a tool for preclinical assessment of new DNA methylation modulators.