title: Cytochrome P450s in human immune cells regulate IL-22 and c-Kit via an AHR feedback loop.
abstract: The mechanisms how environmental compounds influence the human immune system are unknown. The environmentally sensitive transcription factor aryl hydrocarbon receptor (AHR) has immune-modulating functions and responds to small molecules. Cytochrome P4501 enzymes (CYP1) act downstream of the AHR and metabolize small molecules. However, it is currently unknown whether CYP1 activity is relevant for immune modulation. We studied the interdependence of CYP1 and AHR in human primary immune cells using pharmacological methods. CYP1 inhibition increased the expression levels of the stem cell factor receptor (c-Kit) and interleukin (IL)-22 but decreased IL-17. Single cell analyses showed that CYP1 inhibition especially promoted CD4+helper T (Th) cells that co-express c-Kit and IL-22 simultaneously. The addition of an AHR antagonist reversed all these effects. In addition to T cells, we screened other human immune cells for CYP and found cell-specific fingerprints, suggesting that similar mechanisms are present in multiple immune cells. We describe a feedback loop yet unknown in human immune cells where CYP1 inhibition resulted in an altered AHR-dependent immune response. This mechanism relates CYP1-dependent metabolism of environmental small molecules to human immunity.
authors.affiliation: Center of Allergy &Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Effner
authors.affiliation: Chair and Institute of Environmental Medicine (UNIKA-T), Technische Universität München and Helmholtz Center Munich, Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hiller
authors.affiliation: Center of Allergy &Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Eyerich
authors.affiliation: Chair and Institute of Environmental Medicine (UNIKA-T), Technische Universität München and Helmholtz Center Munich, Munich, Germany.|CK-CARE, Christine Kühne - Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Traidl-Hoffmann
authors.affiliation: Department of Dermatology and Allergy, Technische Universität München, Munich, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Brockow
authors.affiliation: Division of Allergy and Clinical Immunology, Department of Medicine, University of Salerno, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Triggiani
authors.affiliation: Center of Allergy &Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany.
authors.forename: Heidrun
authors.initials: H
authors.lastname: Behrendt
authors.affiliation: Center of Allergy &Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany.
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Schmidt-Weber
authors.affiliation: Center of Allergy &Environment (ZAUM), Member of the German Center for Lung Research (DZL), Technische Universität München/Helmholtz Center, Munich, Germany.|CK-CARE, Christine Kühne - Center for Allergy Research and Education, Davos, Switzerland.
authors.forename: Jeroen T M
authors.initials: JT
authors.lastname: Buters
mesh_terms: D000072461:Cytochrome P450 Family 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D007378:Interleukins / Q000378:metabolism*; D061251:Primary Cell Culture; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D000072461:Cytochrome P450 Family 1; D007378:Interleukins; D019009:Proto-Oncogene Proteins c-kit; D018336:Receptors, Aryl Hydrocarbon; D000097043:Interleukin-22