Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand that Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling

Abstract

Inflammatory signaling plays a key role in tumor progression, and the pleiotropic cytokine interleukin-6 (IL-6) is an important mediator of protumorigenic properties. Activation of the aryl hydrocarbon receptor (AHR) with exogenous ligands coupled with inflammatory signals can lead to synergistic induction of IL6 expression in tumor cells. Whether there are endogenous AHR ligands that can mediate IL6 production remains to be established. The indoleamine-2,3-dioxygenase pathway is a tryptophan oxidation pathway that is involved in controlling immune tolerance, which also aids in tumor escape. We screened the metabolites of this pathway for their ability to activate the AHR; results revealed that kynurenic acid (KA) is an efficient agonist for the human AHR. Structure-activity studies further indicate that the carboxylic acid group is required for significant agonist activity. KA is capable of inducing CYP1A1 messenger RNA levels in HepG2 cells and inducing CYP1A-mediated metabolism in primary human hepatocytes. In a human dioxin response element-driven stable reporter cell line, the EC(25) was observed to be 104nM, while in a mouse stable reporter cell line, the EC(25) was 10muM. AHR ligand competition binding assays revealed that KA is a ligand for the AHR. Treatment of MCF-7 cells with interleukin-1beta and a physiologically relevant concentration of KA (e.g., 100nM) leads to induction of IL6 expression that is largely dependent on AHR expression. Our findings have established that KA is a potent AHR endogenous ligand that can induce IL6 production and xenobiotic metabolism in cells at physiologically relevant concentrations.

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

“…At present, kynurenine, kynurenic acid, indoleacetic acid, and indoxyl sulfate-all indolic products of tryptophan metabolism-have been shown to bind to the AhR or induce the expression of AhR response genes, such as CYP1A1. 38,[93][94][95][96][97] Moreover, as shown in Table 3, all four metabolites activate the AhR at concentrations either similar to the highest C max determined in dialysis patients (eg, indole acetic acid) or at levels decisively lower than the C max , for instance indoxyl sulfate. To date, the clinical implications of AhR activation in the setting of CKD development and progression remain unclear, however, it has been postulated that uremic solutes might evoke dioxinlike toxicity, 38 leading to suppression of immune responses, induction of carcinogenesis and accelerating tumor growth, and promoting atherosclerosis.…”

Aryl Hydrocarbon Receptor-Null Allele Mice Have Hematopoietic Stem/Progenitor Cells with Abnormal Characteristics and Functions

“…However, direct relationships between the modulation of known responsive genes and specific functional outcomes in cells/tissues have to be yet determined. Likewise, the normal function of the AhR is not known and true endogenous ligands have not been clearly identified, although recent data suggest likely candidates [7][8][9].…”

Kynurenic acid enhances expression of p21 Waf1/Cip1 in colon cancer HT-29 cells

“…Recently, it was also reported that KYNA is an agonist of aryl hydrocarbon receptor [2]. KYNA was found in human saliva [10], gastric juice, bile, pancreatic juice [15], mucus of rat small intestine [11] and mucus of pig colon [15].…”