The effect of kynurenic acid on the synthesis of selected cytokines by murine splenocytes – in vitro and ex vivo studies

Abstract

Kynurenic acid (KYNA), a secondary product of the kynurenine pathway of tryptophan degradation, known mainly as an endogenous neuroprotectant, shows also immunotropic properties. Some quantities of KYNA are present in food and are effectively absorbed in the gastrointestinal tract. Since the spleen is an important target of dietary immunomodulators, the aim of the study was to determine the effect of exogenous KYNA on murine splenocytes. Splenocytes isolated from adult BALB/c mice were used in the study. Firstly, the effect of increasing KYNA concentrations (0-5 mM) on the viability, and proliferative and cytokine response (interleukin 1β [IL-1β], IL-6, IL-10, tumor necrosis factor α [TNF-α]) of murine splenocytes under in vitro conditions was determined. Then, proliferative and cytokine responses were determined in cells derived from animals receiving kynurenic acid in drinking water at concentrations of 2.5, 25, or 250 mg/l for 7-14 days. Cytokine levels were measured using commercial immunoassay (ELISA) kits, and cell viability and proliferation was determined with MTT reduction assay. Exogenous KYNA was characterised by a low level of cytotoxicity towards murine splenocytes, and was well tolerated by the animals receiving it in drinking water. As expected, it exhibited anti-inflammatory action towards the activated splenocytes, under both in vitro and ex vivo conditions. Surprisingly, however, KYNA itself influenced the activity of resting, non-stimulated cells, exerting an immunostimulant effect in vitro, and an immunosuppressive effect under ex vivo conditions. The obtained results indicate not only anti-inflammatory, but also more complex, immunomodulating properties of KYNA, which require more detailed investigation.

Tryptophan Metabolism through the Kynurenine Pathway is Associated with Endoscopic Inflammation in Ulcerative Colitis

“…It can decrease leukocyte recruitment and production of proinflammatory cytokines in splenocytes in vitro. [25][26][27][28] Notably, there is evidence that it can also negatively regulate TNFα, IL-17, and IL-23. 13,14 A recent publication suggested that KYNA inhibited IL-10 in vitro, IDO1 deficiency was associated with increased IL-10 production, and IL-10 -/-IDO1 -/-mice demonstrated more severe colitis than IDO1 -/or IL10 -/-mice.…”

Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions

“…There are strong indications that the action of KYNA varies depending on whether inflammatory or homeostatic conditions are considered. Under homeostatic conditions, KYNA induced interleukin 6 (IL6) mRNA expression 2 h after treatment in the breast cancer cell line MCF-7 ( 27 ) and cytokine secretion (TNF, IL6, IL1β, and IL10) in primary murine splenocytes after 72 h ( 62 ). A further in vitro study indicated that KYNA may be an early mediator of leukocyte recruitment, acting by triggering the activation of neutrophils as well as the adhesion of monocytes to fibronectin and intercellular adhesion molecule 1 via β1-/β2 integrin ( 63 ).…”

The Role of the Status of Selected Micronutrients in Shaping the Immune Function

“…S1P acts as a signalling factor that regulates the trafficking of immune cells and T-lymphocyte differentiation among others [ 147 , 150 ]. PLP is also a co-factor in the production of kynurenine and kynurenic acid from tryptophan that have shown anti-inflammatory and immunomodulatory effects [ 147 , 151 ].…”