Kynurenic acid downregulates IL-17/1L-23 axis in vitro

Mol Cell Biochem. 2017 Jul;431(1-2):55-65. doi: 10.1007/s11010-017-2975-3. Epub 2017 Mar 11.

Abstract

Exploring the function of interleukin (IL) 17 and related cytokine interactions have been proven useful toward understanding the role of inflammation in autoimmune diseases. Production of the inflammatory cytokine IL-23 by dendritic cells (DC's) has been shown to promote IL-17 expression by Th17 cells. It is well established that Th17 cells play an important role in several autoimmune diseases including psoriasis and alopecia. Our recent investigations have suggested that Kynurenine-rich environment can shift a pro-inflammatory response to an anti-inflammatory response, as is the case in the presence of the enzyme Indoleamine 2,3 dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation and Kynurenine (Kyn) production. In this study, we sought to explore the potential role of kynurenic acid (KynA), in modulating the expression of IL-23 and IL-17 by DCs and CD4+ cells, respectively. The result of flow cytometry demonstrated that the frequency of IL-23-producing DCs is reduced with 100 µg/ml of KynA as compared with that of LPS-stimulated DCs. KynA (100 μg/ml) addition to activated T cells significantly decreased the level of IL-17 mRNA and frequency of IL-17+ T cells as compared to that of concanavalin (Con) A-activated T cells. To examine the mechanism of the suppressive role of KynA on IL-23/IL-17 in these cells, cells were treated with 3 μM G-protein-coupled receptor35 (GPCR35) inhibitor (CID), for 60 min. The result showed that the reduction of both adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) by KynA is involved in suppression of LPS-induced IL-23p19 expression. Since GPCR35 is also detected on T cells; therefore, it is concluded that KynA plays an important role in modulating the expression of IL-23 and IL-17 in DCs and Th17 cells through inhibiting GPCR35 and downregulation of both AC and cAMP.

Keywords: Dendritic cells; IL-17; IL-23; Inflammation; Kyn; KynA.

MeSH terms

  • Animals
  • Cyclic AMP / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Interleukin-17 / immunology*
  • Interleukin-23 / immunology*
  • Kynurenic Acid / pharmacology*
  • Male
  • Mice
  • Second Messenger Systems / drug effects*
  • Second Messenger Systems / immunology
  • Th17 Cells / cytology
  • Th17 Cells / immunology*

Substances

  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Interleukin-17
  • Interleukin-23
  • Cyclic AMP
  • Kynurenic Acid