Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells
journal contributionposted on 14.09.2020, 10:07 by Chris Schiering, Anne Vonk, Srustidhar Das, Brigitta Stockinger, Emma Wincent
The aryl hydrocarbon receptor (AHR) controls interleukin 22 production by T helper 17 cells (Th17). IL-22 contributes to intestinal homeostasis but has also been implicated in chronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes which in turn play an important feedback role that curtails the duration of AHR signaling by metabolizing AHR ligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signaling by disrupting metabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-) we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cells is profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s).
Aryl hydrocarbon receptorCytochrome P4501Enzyme inhibitionInterleukin 22Synergistic receptor activationT helper 17 cellsAnimalsCarbazolesCell DifferentiationCytochrome P450 Family 1Dose-Response Relationship, DrugEnvironmental PollutantsGene ExpressionInterleukinsMaleMice, Inbred C57BLMice, KnockoutPolycyclic Aromatic HydrocarbonsReceptors, Aryl HydrocarbonTh17 CellsTime FactorsStockinger FC001159FC-ackBRF-ackPharmacology & Pharmacy1115 Pharmacology and Pharmaceutical Sciences0601 Biochemistry and Cell Biology