The Opposite Effects of Kynurenic Acid and Different Kynurenic Acid Analogs on Tumor Necrosis Factor-α (TNF-α) Production and Tumor Necrosis Factor-Stimulated Gene-6 (TSG-6) Expression.

Yvette Mándi,Timea Mosolygó,László Vécsei,Ferenc Fülöp,Ildikó Lantos,Katalin Burián,Bálint Lőrinczi,Valéria Endrész,István Szatmári,Attila Balog

doi:10.3389/fimmu.2019.01406

Yvette Mándi, Timea Mosolygó + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2019.01406

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Abstract

Purpose: The investigation of anti-inflammatory and immunosuppressive functions of Kynurenic acid (KYNA) is now in focus. There is also substantial evidence that TSG-6 has an anti-inflammatory activity. Therefore, in the present study, we compared the effects of newly synthetized KYNA analogs on the TNF-α production in U-937 monocytic cells in correlation with the effects on the TSG-6 expression.Methods: TNF-α production was measured by ELISA, the TSG-6 expression was determined by RTqPCR method. As cytokine inducers Staphylococcus aureus and Chlamydia pneumoniae were used.Results: KYNA and KYNA analogs attenuated TNF-α production and increased TSG-6 mRNA expression in U-937 cells stimulated by heat inactivated Staphylococcus aureus. In contrast, KYNA and some of the KYNA analogs increased the TNF-α production of C. pneumoniae infected U-937 cells; however, the newly synthetized analogs (SZR104, SZR 105, and SZR 109) exerted significant inhibitory effects on the TNF-α synthesis. The inhibitory and stimulatory effects correlated inversely with the TSG-6 expression.Conclusions: TSG-6 expression following activation with bacterial components could participate in the suppression of inflammatory cytokines, such as TNF-α, 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. KYNA and KYNA analogs have an important role in influencing TSG-6 expression, and there is a possible benefit of targeting TSG-6 expression by kynurenines in inflammatory conditions following infections.

Highlights

There is an increasing interest in the role of kynurenines in the immune function
We focused on the potential correlation between the effects on the Tumor necrosis factor -stimulated gene-6 (TSG-6) (TNFα- stimulated gene 6) expression and the influence, i.e., the suppression, of TNF-α production by different Kynurenic acid (KYNA) analogs
For TNF-α and TSG-6 induction, 5 × 105 U-937 cells/mL were infected with 107 heat inactivated Staphylococcus aureus (S.aureus), or with 5 multiplicity of infection (MOI) Chlamydia pneumoniae

Summary

Introduction

The kynurenine pathway is a regulator of both innate and adaptive immune responses, and the tryptophan metabolism kynurenine and production reflect a crucial interface between the immune and nervous systems [1, 2]. Kynurenic acid (KYNA) is one of the products of the kynurenine pathway of tryptophan metabolism [3,4,5]. KYNA as an antagonist of ionotropic glutamate receptors N-methyl-D-aspartate (NMDA) and the α7 nicotinic acetylcholine receptor (α7nAchR) exert neuroprotective effects [2, 4,5,6,7,8,9,10]. KYNA acts both as a blocker of the glycine co-agonistic site of the NMDA receptor and as a non-competitive inhibitor of the α7 nicotinic acetylcholine receptor [11]. It has been proved that these immunomodulatory properties are based on the signaling by G-protein-coupled receptor 35 (GP35) and aryl hydrocarbon receptor (AHR)-mediated pathways ys [2, 12,13,14]

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