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The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0003-1045-376X
Number of Authors: 22018 (English)In: Critical reviews in toxicology, ISSN 1040-8444, E-ISSN 1547-6898, Vol. 48, no 7, p. 555-574Article, review/survey (Refereed) Published
Abstract [en]

The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.

Place, publisher, year, edition, pages
2018. Vol. 48, no 7, p. 555-574
Keywords [en]
6-Formylindolo[3, 2-b]carbazole, aryl hydrocarbon receptor, tryptophan, endogenous ligand, immunity, cancer, toxicity, feedback loop, cytochrome P4501A1, CYP1A1, TCDD, metabolism
National Category
Biological Sciences Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:su:diva-163740DOI: 10.1080/10408444.2018.1493086ISI: 000453847600004PubMedID: 30226107OAI: oai:DiVA.org:su-163740DiVA, id: diva2:1276943
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved

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