AB0107 INVESTIGATION OF THE EFFECTS OF KYNURENIC ACID ANALOGS IN RHEUMATOID ARTHRITIS
Authors: B. Varga, A. Balog, F. Fülöp, L. Vécsei, Y. Mándi
Journal: Annals of the Rheumatic Diseases (2020)

Background: The investigation of anti-inflammatory and immunosuppressive functions of kynurenic acid (KYNA) is now in focus. Previously, we demonstrated the opposite effects of KYNA and different KYNA analogs on tumor necrosis factor-α (TNF-α) production and tumor necrosis factor-stimulated gene-6 (TSG-6) expression in U-937 monocytic cells. The potential effect of KYNA analogs on further immune mediators including alarmins (S100A12=EN-RAGE and S100A8/9=calprotectin), and on human neutrofil peptide 1-3(α-defensin) production has not been investigated. Objectives: Therefore, in the present study, we compared the effects of newly synthesized KYNA analog on the TNF-α, alarmins and α-defensin production, correlation with the effects on the TSG-6 expression in rheumatoid arthritis (RA). Methods: 93 RA patients were involved and divided subgroups based on DAS28 activity score. Peripheral blood mononuclear cells (PBMC) was isolated from RA patients and healthy controls. As cytokine inducers heat inactivated Staphylococcus aureus (SA1) were used. In parallel in vitro experiments, the SA1 induced PBMCs were pretreated with a newly synthesized KYNA analog (compound SZR-72 was synthesized by direct amidation of KYNA). The concentrations of the above mentioned inflammatory mediators in the supernatants were quantified by using ELISA kits and the TSG-6 expression was also determined by RTqPCR method. Results: The SA1 induced TNF-α, EN-RAGE, calprotectin and α-defensin production was significantly higher in RA patients’ group than in healthy controls. KYNA analog attenuated the SA1 induced TNF-α, EN-RAGE, calprotectin and α-defensin production, and increased TSG-6 production and TSG-6 mRNA expression in PBMC cells from RA patients. The SA1 induced TNF-α and TSG-6 production correlated with the DAS28 activity score. The TNF-α inhibitory effect of the KYNA analog correlated inversely with the TSG-6 stimulatory effect in all subgroups of RA patients based on DAS28 activity score. Conclusion: TSG-6 expression could participate in the suppression of inflammatory cytokines, such as TNF-α, EN-RAGE, calprotectin and α-defensin. We suppose that the elevation of the TSG-6 expression by KYNA and especially by new KYNA analogs might be one of the mechanisms that are responsible for their suppressive effect on TNF-α production as a feedback mechanism in RA. KYNA and KYNA analogs have an important role in influencing TSG-6 expression, and there is a possible benefit with potential therapeutic consequence of targeting TSG-6 expression by kynurenines in inflammatory conditions in RA. References: [1]Mándi Y, Endrész V, Mosolygó T, Burián K, Lantos I, Fülöp F, Szatmári I, Lőrinczi B, Balog A, Vécsei L, The Opposite Effects of Kynurenic Acid and Different Kynurenic Acid Analogs on Tumor Necrosis Factor-a (TNF-a) Production and Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6) Expression. Frontiers in Immunology. doi: 10.3389/fimmu.2019.01406 Acknowledgments: This work was supported by GINOP 2.3.2-2015-16-00034 Disclosure of Interests: None declared