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

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Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand That Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling TOXICOLOGICAL SCIENCES 115(1), 89–97 (2010) doi:10.1093/toxsci/kfq024 Advance Access publication January 27, 2010 Kynurenic Acid Is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand that Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling Brett C. DiNatale, Iain A. Murray, Jennifer C. Schroeder, Colin A. Flaveny, Tejas S. Lahoti, Elizabeth M. Laurenzana, Curtis J. Omiecinski, and Gary H. Perdew1 Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, Pennsylvania 16803 Downloaded from 1 To whom correspondence should be addressed at Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, 309 Life Sciences Building, University Park, PA 16802. Fax: (814) 863-1696. E-mail: [email protected]. Received November 25, 2009; accepted January 20, 2010 ligands. The prototypic high-affinity ligand, 2,3,7,8- toxsci.oxfordjournals.org Inflammatory signaling plays a key role in tumor progression, tetrachlorodibenzo-p-dioxin (TCDD), mediates its toxicity and the pleiotropic cytokine interleukin-6 (IL-6) is an important through continual prolonged activation of the AHR. This mediator of protumorigenic properties. Activation of the aryl hyperactivation of the AHR leads to a myriad of transcriptional hydrocarbon receptor (AHR) with exogenous ligands coupled with inflammatory signals can lead to synergistic induction of IL6 responses resulting in a wide range of toxicities. AHR- expression in tumor cells. Whether there are endogenous AHR mediated liver toxicity requires that the AHR bind to its ligands that can mediate IL6 production remains to be estab- cognate response element (Bunger et al., 2008). The AHR resides in the cytoplasm of the cell bound to a dimer of HSP90 lished. The indoleamine-2,3-dioxygenase pathway is a tryptophan at University of Washington on March 4, 2011 oxidation pathway that is involved in controlling immune and the X-associated protein 2 (Meyer et al., 1998; Perdew, tolerance, which also aids in tumor escape. We screened the 1988). Following ligand binding, the AHR translocates into the metabolites of this pathway for their ability to activate the AHR; nucleus and dimerizes with ARNT. This heterodimer then results revealed that kynurenic acid (KA) is an efficient agonist for binds to dioxin responsive elements (DRE), leading to altered the human AHR. Structure-activity studies further indicate that gene expression. The most studied group of genes directly the carboxylic acid group is required for significant agonist regulated by the AHR are involved in xenobiotic metabolism activity. KA is capable of inducing CYP1A1 messenger RNA and includes CYP1A1, CYP1A2, and CYP1B1 (Beischlag levels in HepG2 cells and inducing CYP1A-mediated metabolism in primary human hepatocytes. In a human dioxin response et al., 2008). A number of other genes regulated by the AHR are involved in an array of distinct pathways. For example, the element–driven stable reporter cell line, the EC25 was observed to be 104nM, while in a mouse stable reporter cell line, the EC25 was genes Snai 2, Ereg, and Cdkn1b are directly induced through 10mM. AHR ligand competition binding assays revealed that KA AHR/ARNT binding to DRE sites. DNA microarray experi- is a ligand for the AHR. Treatment of MCF-7 cells with ments that examine gene regulation following activation of the interleukin-1b and a physiologically relevant concentration of AHR reveal that, among the gene expression levels that are KA (e.g., 100nM) leads to induction of IL6 expression that is altered, a significant number of genes are both induced and largely dependent on AHR expression. Our findings have repressed (Sato et al., 2008). Recently, the AHR has been established that KA is a potent AHR endogenous ligand that shown to repress acute-phase gene expression in a DRE- can induce IL6 production and xenobiotic metabolism in cells at independent manner, probably through protein-protein inter- physiologically relevant concentrations. actions (Patel et al., 2009). This observation underscores the Key Words: aryl hydrocarbon receptor; kynurenic acid; IDO; TCDD; IL6. complexity of gene regulation mediated by the AHR. An important question that remains to be resolved is the identity of key endogenous ligands for the AHR. A number of endogenous compounds have been shown to be AHR ligands, The aryl hydrocarbon receptor (AHR) is a member of the including indirubin, bilirubin, 7-ketocholesterol, and canthaxan- basic helix-loop-helix Per/ARNT/Sim family of transcription thin (for review, see Denison and Nagy, 2003). Recently, factors. The AHR is the only known member of this family that arachidonic acid derivatives, including 12(R)HETE, have been is a ligand-activated transcription factor, regulated through the shown to activate the AHR (Chiaro et al., 2008a,b).Whether these binding of structurally diverse endogenous and exogenous compounds are present at the physiological levels that would lead Ó The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected] 90 DINATALE ET AL. to a significant amount of AHR activation remains unclear. While Cell culture. HepG2 40/6 and H1L1.1c2 cells were maintained in alpha indirubin was originally identified in human urine as a potent minimum essential medium, supplemented with 8% fetal bovine serum activator of the AHR, its rapid metabolism leads to it only being (Hyclone Laboratory, Logan, UT), 1000 U/ml penicillin, and 0.1 mg/ml streptomycin (Sigma). MCF-7 breast tumor cells were maintained as previously present in urine at a low concentration of 0.2nM (Adachi et al., described (Hollingshead et al., 2008). 2001). The other endogenous ligands mentioned above are Primary human hepatocytes. Female primary human hepatocytes from relatively weak ligands and are not likely to significantly activate two different donors were obtained from the University of Pittsburgh, through the AHR under normal physiological homeostasis. However, the Liver Tissue Cell Distribution System, National Institutes of Health during jaundice, bilirubin levels are likely to be elevated Contract #N01-DK-7-0004/HHSN267200700004C. Culture details have been sufficiently to activate the AHR in liver, resulting in increased reported previously (Olsavsky et al., 2007). Forty-eight hours following metabolism (Phelan et al., 1998; Togawa et al.,2008). Matrigel additions, cells were exposed to ligands. We have recently observed that the combination of AHR ligands Stable reporter luciferase assay. Assays were performed using the human and an inflammatory signal leads to synergistic induction of hepatoma HepG2 40/6 and mouse hepatoma H1L1.1c2 stable reporter cell interleukin-6 (IL-6) expression in MCF-7 cells (Hollingshead et al., lines, as described previously (Chiaro et al., 2008b; Garrison et al., 1996). Each cell line had the DRE-driven reporter vector pGudLuc 6.1 or pGudLuc 1.1 2008). While potent exogenous AHR ligands can mediate this stably integrated, respectively. Downloaded from activity, it has not been established whether there are endogenous Ligand-binding assay and transgenic mice. AHR ligand–binding assays AHR ligands at physiological levels that can similarly mediate IL6 were performed as described previously, as was the development of the induction in tumor cells. Our rationale for assessing tryptophan AHRTtrCreAlbAhrfx/fx mouse model from which liver cytosol was used as derivatives follows previous studies, which demonstrated that this a source for human AHR (Flaveny et al., 2009). In this mouse line, the mouse amino acid may be a common precursor for the synthesis of human AHR has been deleted from hepatocytes, and the human AHR is expressed AHR ligands. A number of tryptophan metabolites and indole from the transgene driven by a hepatocyte-specific promoter. toxsci.oxfordjournals.org derivatives exhibit ligand-binding activity toward the human AHR, RNA isolation and real-time PCR. Real-time reverse transcriptase-PCR including indirubin and 6-formylindolo[3,2-b]carbazole (FICZ). was performed as previously described (Chiaro et al., 2008b). Primers used for Such products can elicit AHR signaling, as determined by real-time RT-PCR analysis are listed in Supplementary table 1. induction of the AHR target gene CYP1A1. However, while Gene silencing. AHR protein levels were decreased using the Dharmacon detectable in humans, both indirubin and FICZ are generated in a On-Target plus small interfering RNA (siRNA) oligo (Dharmacon; J004990- 07). Electroporation was performed using the Amaxa nucleofection system. spontaneous nonregulated fashion through acid condensation or as Briefly, cells were washed and suspended at a concentration of 3 3 106 per 100 an ultraviolet-mediated photoproduct, respectively. Such unregu- ll of nucleofection solution. The siRNA was added to the sample for a final at University of Washington on March 4, 2011 lated synthesis is unlikely to be compatible with the coordinated concentration of 2lM. Cells were electroporated using the manufacturer’s high physiological regulation of AHR signaling. Thus, we opted to efficiency MCF-7 program and plated into six-well plates. examine endogenous tryptophan derivatives that arise from Protein electrophoresis and immunoblot analysis. Whole-cell extracts regulated synthesis and demonstrate physiological activity, which were prepared and resolved by tricine-SDS-polyacrylamide gel
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