Myeloid human cell lines lack functional regulation of aryl hydrocarbon receptor-dependent phase I genes

Abstract

SummaryPrimary dendritic cells and myeloid cell lines are used to assess the skin sensitization hazard in in vitro approaches. The aryl hydrocarbon receptor (AhR) modulates expression of CYP enzymes, which play a significant role in the bioactivation of various xenobiotics. These studies revealed a strong constitutive expression of the AhR in primary human monocytes, monocyte-derived immature dendritic cells (iDC) and cord blood-derived Langerhans cells (LC). In contrast, mRNA and protein expression of AhR was hardly detectable in the cell lines THP-1 and MUTZ-3. U937 cells and MUTZ-3-derived dendritic (MUTZ-DC) or Langerhans cells (MUTZ-LC) showed about half the expression of AhR compared to iDC. Incubation of cells with the specific AhR-inducer benzo [a]anthracene resulted in an upregulation of CYP and IL-1β mRNA expression in primary monocytes and iDC. CYP1A1 but not CYP1B1 and IL-1β expression was increased by benzo [a]anthracene in these cell lines except for U937 cells. AhR-independent CYP genes were not regulated by benzo [a]anthracene. Constitutive mRNA expression of other non AhR-dependent CYP enzymes was higher in some of the cell lines compared to the corresponding primary cells. This study demonstrates significant differences in expression and regulation of phase I genes in cell lines currently used for in vitro skin sensitization hazard assessment compared to primary cells. Additional studies are required regarding the combination of cutaneous xenobiotic metabolizing enzymes and APC-sensitization for the development of valid in vitro models for skin sensitization assessment.

AhR mediates an anti‐inflammatory feedback mechanism in human Langerhans cells involving FcεRI and IDO

“…We could show an increase in CYP1A and CYP1B1 expression in CD34LC upon treatment with the AhR ligand FICZ. This is in accordance with reports showing inducible expression of CYP1B1 in freshly isolated human LC after 7,12‐dimethylbenz[a]anthracene stimulation and induction of CYP1A1 in cord blood‐derived LC as well as in human monocytes and DC …”

“…These cells were used to further analyze the role of AhR activation in skin APC. The AhR is expressed on CD34LC as reported . Furthermore, we could detect that the AhRR is also expressed in human CD34LC (Figure ).…”

“…Constitutive expression of the AhR has been reported in human monocytes, immature DC, and cord blood‐derived LC . To study the role of AhR signaling in human epidermal APC, we analyzed AhR and AhRR expression in skin‐derived, CD1a + /Langerin + LC.…”

Cow’s milk protein β-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells

“…Molecular studies also showed that the tolerogenic aryl hydrocarbon receptor pathway was activated. AhR expression levels vary in immune cells, with high expression levels found in monocytes, 82 dendritic cells, macrophages, 83 and B cells. 84,85 Within the T-cell compartments, T H 17 cells, and to a lesser extent Treg cells, express AhR.…”

Aryl hydrocarbon receptor signalling in the skin and adverse vemurafenib effects

“…On the other side, the AhR‐dependent signalling pathway is connected with other signalling pathways such as the antioxidant response by Nrf2 . Further on, the AhR interacts with several cytokines and growth factors including the epidermal growth factor depending signalling, TNF‐α and TGF‐β, and finally, the AhR is expressed also in immunocompetent cells such as antigen‐presenting monocytes or macrophages as well as T lymphocytes, in particular in Th17‐cells . Therefore, it ruled out that the AhR functions on the one side as a sensor not only for multiple exogenous chemical agents but also for UV light and the microbiome; on the other side, this receptor influences in the target organs such as the skin multiple physiological and pathophysiological processes, e.g.…”