Abstract
The aryl hydrocarbon receptor (AHR) binds major physiological modifiers of the immune system. The endogenous 6-formylindolo[3,2-b]carbazole (FICZ), which binds with higher affinity than any other compound yet tested, including TCDD, plays a well-documented role in maintaining the homeostasis of the intestines and skin. The effects of transient activation of AHR by FICZ differ from those associated with continuous stimulation and, depending on the dose, include either differentiation into T helper 17 cells that express proinflammatory cytokines or into regulatory T cells or macrophages with anti-inflammatory properties. Moreover, in experimental models of human diseases high doses stimulate the production of immunosuppressive cytokines and suppress pathogenic autoimmunity. In our earlier studies we characterized the formation of FICZ from tryptophan via the precursor molecules indole-3-pyruvate and indole-3-acetaldehyde. In the gut formation of these precursor molecules is catalyzed by microbial aromatic-amino-acid transaminase ArAT. Interestingly, tryptophan can also be converted into indole-3-pyruvate by the amino-acid catabolizing enzyme interleukin-4 induced gene 1 (IL4I1), which is secreted by host immune cells. By thus generating derivatives of tryptophan that activate AHR, IL4I1 may have a role to play in anti-inflammatory responses, as well as in a tumor escape mechanism that reduces survival in cancer patients. The realization that FICZ can be produced from tryptophan by sunlight, by enzymes expressed in our cells (IL4I1), and by microorganisms as well makes it highly likely that this compound is ubiquitous in humans. A diurnal oscillation in the level of FICZ that depends on the production by the fluctuating number of microbes might influence not only intestinal and dermal immunity locally, but also systemic immunity.
Highlights
The aryl hydrocarbon receptor (AHR) regulates numerous enzymes and transcriptional programs, helping to balance a variety of physiological functions
FICZ is a pure AHR agonist and at the same time, FICZ is an exceptionally good substrate for the CYP1A1, 1A2, and 1B1 enzymes of the cytochrome P-450 family leading to its rapid degradation and formation of metabolites that are found in human urine (Wincent et al, 2009)
The metabolism of FICZ by cytochrome P450 and phase II enzymes and its binding to the AHR and other receptors [reviewed in Rannug and Rannug (2018)] that subsequently act as transcription factors resembles regulation of the steady-state levels of hormones like estrogen and cortisol and certain vitamins like vitamins A, B, and D
Summary
Reviewed by: Yuseok Moon, Pusan National University, South Korea Courtney E. Received: 13 September 2021 Accepted: 11 January 2022 Published: 27 January 2022 Both Endogenously and by Microorganisms, can Either Promote or Restrain Inflammatory Responses. The effects of transient activation of AHR by FICZ differ from those associated with continuous stimulation and, depending on the dose, include either differentiation into T helper 17 cells that express proinflammatory cytokines or into regulatory T cells or macrophages with antiinflammatory properties. Tryptophan can be converted into indole-3-pyruvate by the amino-acid catabolizing enzyme interleukin induced gene 1 (IL4I1), which is secreted by host immune cells. The realization that FICZ can be produced from tryptophan by sunlight, by enzymes expressed in our cells (IL4I1), and by microorganisms as well makes it highly likely that this compound is ubiquitous in humans.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
