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.

fibroblast-like synovial cells, rheumatoid arthritis, DNA methylation, cytokines, genistein, hydralazine, ademethionine

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