The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

Figures & data

Figure 1. Formation pathways of 6-formylindolo[3,2-b]carbazole (FICZ) and indolo[3,2-b]carbazole-6-carboxylic acid (CICZ) from tryptophan directly or from the tryptophan metabolites tryptamine and indolo-3-pyruvic acid, respectively, via the common precursor indolo-3-acetaldehyde. All three pathways produce the same precursor of FICZ.

Figure 2. The FICZ/AHR/CYP1A1 feedback loop can be blocked by various types of inhibitors. Abbreviations: AHR, aryl hydrocarbon receptor; AHRE, AHR response element; ARNT, AHR nuclear translocator; CYP1A1, cytochrome P4501A1; FICZ, 6-formylindolo[3,2-b]carbazole; kcat/Km, catalytic efficiency; Kd, dissociation constant; PAMPs, pathogen associated molecular patterns; ROS, reactive oxygen species.

Table 1. Effects by FICZ on disease severity in murine models of human diseases.

Disease	Murine model	FICZ treatment	Biological responses	Disease outcome	Reference
Allergy	Passive systemic anaphylaxis induced with 2,4-dinitrophenyl (DNP)-specific IgE in mice	One i.v. administration of 100 µg FICZ kg^−1 during the challenge phase	↑ Plasma histamine	Increased severity	(Sibilano et al. 2012)
		Two i.v. administrations of 100 µg FICZ kg^−1 3 and 16 h before antigen challenge	↓ Plasma histamine	Less severity
	Passive cutaneous anaphylaxis induced with ovalbumin (OVA)-specific IgE in mice	One intra-dermal administration of 0.03 or 0.3 µg FICZ kg^−1 during the sensitization phase	↑ Vascular leakage	Increased severity	(Zhou et al. 2013)
	Peanut allergy in mice	Multiple i.p. injections of 50 or 500 µg FICZ kg^−1 before and during sensitization to antigen	No effect	No difference	(Schulz et al. 2012)
	OVA-induced allergic asthma in mice	One i.p. injection of 3 or 30 µg FICZ kg^−1 during the sensitization phase	↓ IL-4, IL-5, IgE	Less severity	(Jeong et al. 2012)
Atopic dermatitis	Mite-induced topic dermatitis in mice	Topical treatment with 100 mg of an ointment containing 1 µM FICZ three times a week for 2 weeks	↓ IL-22, IFNγ	Less severity	(Kiyomatsu-Oda et al. 2018)
Cancer	Tumor growth in wild type mice injected with murine lymphoma RMA-S cells	Three i.p. injections of 150 μg FICZ kg^−1	↑ NK cells, reduced tumor growth	Less severity	(Shin et al. 2013)
	Growth of tumors in immune deficient recombinase-activating gene 1 (RAG1) knock out mice injected with B16 melanoma cells	Three i.p. injections of 150 μg FICZ kg^−1	↓ Tumor cells and lung metastases	Less severity
Diabetes	Mouse streptozotocin (STZ) model	Five i.p. injections of 5.7 µg FICZ kg^−1	↑ Foxp3	Less severity	(Abu-Rezq and Millar 2013)
Graft-versus-host disease (GVHD)	A parent-into-F1 model of GVHD	Four i.p. injections of 10 mg FICZ kg^−1	↑ Foxp3	Less severity	(Ehrlich et al. 2018)
Inflammatory bowel disease (IBD)	Dextran sulfate sodium (DSS)- or trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice	One i.p. injection of 50 µg FICZ kg^−1	↑ IL-22 ↓ IL-17, IFNγ, TNFα	Less severity	(Monteleone et al. 2011)
	T cell transfer to immune deficient RAG1 knock out mice	Five i.p. injections of 50 µg FICZ kg^−1	↑ IL-22 ↓ IFNγ	Less severity	(Monteleone, Marafini, et al. 2016)
	TNBS-induced intestinal fibrosis in mice	Seven i.p. injections of 50 µg FICZ kg^−1	↓ IL-17, TNFα	Less severity	(Monteleone, Zorzi, et al. 2016)
	DSS-induced colitis in mice	Five i.p. injections of 50 µg FICZ kg^−1	↓ IL-7	Less severity	(Ji et al. 2015)
	DSS-induced colitis in mice	Five i.p. injections of 50 µg FICZ kg^−1	↑ IL-10 ↓ IFNγ	Less severity	(Chen et al. 2017)
	DSS-induced colitis in mice deficient in the caspase recruitment domain family member 9 (CARD9) protein	One i.p. injection of 50 µg FICZ kg^−1	↑ IL-22	Less severity	(Lamas et al. 2016)
Multiple sclerosis (MS)	Experimental autoimmune encephalomyelitis (EAE) in mice	One subcutaneous administration of 30 µg FICZ kg^−1	↑ IL-17	Increased severity	(Veldhoen et al. 2008)
		One i.p. injection of 50 µg FICZ kg^−1	↑ IL-17	Increased severity	(Quintana et al. 2008)
		One i.p. injection of 10 mg FICZ kg^−1	↓ IL-17 ↑ IL-10	Less severity	(Duarte et al. 2013)
Peritonitis	Alum-induced peritonitis in mice	One i.p. injection of 200 µg FICZ kg^−1	↓ IL-1β, TNFα, IL-6	Less severity	(Huai et al. 2014)
Psoriasis	Mouse imiquimod (IMQ) model	Daily i.p. injections of 100 µg FICZ kg^−1 over the course of IMQ treatments	↓ IL-22, IL-17	Less severity	(Di Meglio et al. 2014)
		Daily topical applications of 10 ng of FICZ over the course of the IMQ treatment	↓ IL-17	Less severity	(Smith, Jayawickreme, et al. 2017)
Rheumatoid arthritis	Collagen-induced arthritis in transgenic mice carrying human shared epitope-coding alleles	One weekly i.p. injection of 28 µg FICZ kg^−1 for the entire disease course	↑ IL-17, osteoclast infiltration	Increased severity	(Fu et al. 2018)

Figure 3. Activation of the interleukin 22 (IL-22)–IL-22 receptor (IL-22R) pathway by FICZ can regulate immunity, inflammation and tissue homeostasis at immune barriers of, e.g. the skin, lung, and intestine. (1). FICZ formed externally from tryptophan, e.g. by enzyme-catalyzed conversions in microorganisms and by UV-light exposure or taken up from the diet, is efficiently metabolized and cleared in epithelial cells at barrier surfaces after AHR-mediated upregulation of the CYP1A1 enzyme. (2). FICZ formed from tryptophan through host metabolism or added systemically, e.g. via intraperitoneal injection, activates AHR-mediated formation of IL-22 in various immune cells. IL-22 regulates immune responses via ligation of the IL-22R on epithelial cells leading to release of tissue specific cytokines, chemokines and antimicrobial agents. (3). FICZ formed externally may also activate the IL-22–IL-22R pathway if CYP1A1 inhibitors are present that inhibit the clearance of FICZ. For abbreviations, see Figure 2.

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