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How did FICZ become the ultimate ligand for AHR?
6-Formylindolo[3,2-b]carbazole (FICZ) is a chemical compound with the molecular formula C19H12N2O and exhibits extremely high affinity in binding to the aryl hydrocarbon receptor (AHR). Its comprehensive dissociation constant is ( Kd) up to 7 x 10-11M. Initially, FICZ was viewed as a photooxidized derivative of tryptophan and was thought to be an endogenous ligand of AHR. Later, it was further shown that FICZ could also be formed by enzymatic reactions.
FICZ is found in many tryptophan (Trp)-containing solutions, including cell culture media, especially when exposed to UV or visible light.
FICZ formation in humans has also been demonstrated following UVB irradiation of human keratinocytes (HaCaT cells) grown in tryptophan-rich medium. This compound has been identified in patients with certain skin diseases, particularly vitiligo and skin diseases caused by the bacterium Malassezia. FICZ and various other indigo derivatives are produced when Malassezia furfur is grown on tryptophan-only media.
The synthesis and bioproduction mechanisms of FICZ are the focus of research by scientists. In addition to light induction and H2O2 composition, although the presence of FICZ has not been clearly confirmed in mouse colon, its precursors such as indy-3- Propionic acid, indy-3-aldehyde, etc. have been discovered. In addition, a number of enzymatic pathways have been identified to convert tryptophan to FICZ, particularly through reactions in the body.
FICZ is a high-affinity ligand for AHR. When binding to the receptor, it activates multiple target genes, the most famous of which is cytochrome P450 (CYP) 1A1.
On the binding of AHR to FICZ and its effect on gene induction, FICZ has a significant effect, but its induction effect is transient because it is easily metabolized rapidly by CYP1A1. This also makes FICZ a key molecule in regulating AHR signaling, forming a regulatory circuit.
In addition, the multiple roles of FICZ on the immune response are noteworthy. AHR is extremely important in the differentiation of T helper cells. Under special circumstances, FICZ can promote the formation of Th17 cells, thus affecting the immune status. Conversely, FICZ can also expand the number of regulatory T cells, so its potential for use in autoimmunity, infection, and cancer treatment is just emerging.
FICZ is highly expressed in immune barrier organs such as skin, lungs, and intestines, and mice lacking AHR show significant deficiencies in immune function.
In studies, FICZ was shown to increase IL-22 production by specific cells, which is critical for the maintenance of immune barriers. Even in different experimental settings, AHR-stimulated FICZ had significant protective effects against intestinal infection, demonstrating its potential in regulating body immunity.
Although FICZ shows important physiological effects, such as promoting cell regeneration and inhibiting carcinogenesis, when the level of FICZ in the body is too high, it may lead to the excessive production of reactive oxygen species (ROS) and cytotoxicity. These complex effects make FICZ a double-edged sword, and too much FICZ can have adverse effects.
Low concentrations of FICZ can promote cell adaptation and survival, while high concentrations cause cell death.
In summary, the biological functions of FICZ and its role as a ligand for AHR are far-reaching and have become important research topics in the fields of biomedicine and environmental health today. Although its potential therapeutic value cannot be denied, how to balance its benefits and toxicity is still a question worthy of further exploration.
