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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.
Highlights
Introductionaryl hydrocarbon receptor (AHR) has been intensively studied, to date the role of CYP1 metabolism in human immunity is unclear
Atopic diseases and for hematopoietic malignancies[18,28,29,30,31]
The concentration of 1-PP was optimized in a V79 fibroblast CYP1 expression system with stable cDNA-directed expression of recombinant human CYP1A1, CYP1B1 or CYP1A2 enzymes. 1-PP decreased the activity of human CYP1 assayed as ethoxyresorufin deethylase (EROD) in a concentration-dependent manner (Fig. 1b)
Summary
AHR has been intensively studied, to date the role of CYP1 metabolism in human immunity is unclear. We hypothesized that CYP could navigate immune response by degradation of ligands on xeno-sensing transcription factors, and may contribute as metabolic keys to immunity. We examined the interdependence of CYP1 and AHR in human immune cells, especially T cells, and analyzed the cell-specific expression of c-Kit and IL-22 during CYP1 inhibition. To test whether similar mechanisms could be active in multiple immune cells, we screened other human immune cell subtypes for constitutive CYP expression. The CYP pathway is engaged in the metabolism of environmental pollutants, drugs and endogenous molecules, and previously described enzymatic reactions are known to regulate immune responses[32,33,34]. The implications of this environmentally triggered feedback pathway may contribute to new options in immune modulation or in tolerance-promoting treatment strategies
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