Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3',4'-dimethoxy-α-naphthoflavone.

We have characterized previously a class of aryl hydrocarbon receptor (AHR) ligand termed selective AHR modulators (SAhRMs). SAhRMs exhibit anti-inflammatory properties, including suppression of cytokine-mediated acute phase genes (e.g.

Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines.

There is increasing evidence that the aryl hydrocarbon receptor (AHR) plays a role in tumor progression through numerous mechanisms. We have previously shown that, in certain cancer cell lines that are typically nonresponsive to cytokine-mediated IL6 induction, activation of the AHR with the agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin derepresses the IL6 promoter and allows for synergistic induction following IL1β treatment. The mechanism by which this occurs involves liganded AHR binding upstream from the transcription start site and dismissing HDAC-containing corepressor complexes, giving rise to a promoter structure that is more amenable to NF-κB activation.

Mechanistic insights into the events that lead to synergistic induction of interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and inflammatory signaling.

The aryl hydrocarbon receptor (AHR) is the ligand-activated transcription factor responsible for mediating the toxicological effects of dioxin and xenobiotic metabolism. However, recent evidence has implicated the AHR in additional, nonmetabolic physiological processes, including immune regulation. Certain tumor cells are largely nonresponsive to cytokine-mediated induction of the pro-survival cytokine interleukin (IL) 6.

Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling.

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 uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in the regulation of multiple cellular pathways, such as xenobiotic metabolism and Th17 cell differentiation. Identification of key physiologically relevant ligands that regulate AHR function remains to be accomplished. Screening of indole metabolites has identified indoxyl 3-sulfate (I3S) as a potent endogenous ligand that selectively activates the human AHR at nanomolar concentrations in primary human hepatocytes, regulating transcription of multiple genes, including CYP1A1, CYP1A2, CYP1B1, UGT1A1, UGT1A6, IL6, and SAA1.

Antagonism of aryl hydrocarbon receptor signaling by 6,2',4'-trimethoxyflavone.

The aryl hydrocarbon receptor (AHR) is regarded as an important homeostatic transcriptional regulator within physiological and pathophysiological processes, including xenobiotic metabolism, endocrine function, immunity, and cancer. Agonist activation of the AHR is considered deleterious based on toxicological evidence obtained with environmental pollutants, which mediate toxic effects through AHR. However, a multitude of plant-derived constituents, e.

Activation of the antitumor agent aminoflavone (NSC 686288) is mediated by induction of tumor cell cytochrome P450 1A1/1A2.

The present studies were performed to elucidate the mechanism of cytotoxicity of the aminoflavone analog (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (AF; NSC 686288), a novel flavone with potent in vitro and in vivo antiproliferative activity against a number of human tumor cell lines and with a unique pattern of antiproliferative activity in the National Cancer Institute tumor cell line screen. AF was extensively metabolized by cytochrome P450 (P450) 1A1 and 1A2 to several metabolites, one of which was identified by mass spectrometry as a potentially reactive hydroxylamine. Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules.