Balancing intestinal and systemic inflammation through cell type-specific expression of the aryl hydrocarbon receptor repressor.

As a sensor of polyaromatic chemicals the aryl hydrocarbon receptor (AhR) exerts an important role in immune regulation besides its requirement for xenobiotic metabolism. Transcriptional activation of AhR target genes is counterregulated by the AhR repressor (AhRR) but the exact function of the AhRR in vivo is currently unknown. We here show that the AhRR is predominantly expressed in immune cells of the skin and intestine, different from other AhR target genes.

The interleukin-6-type cytokine oncostatin M induces aryl hydrocarbon receptor expression in a STAT3-dependent manner in human HepG2 hepatoma cells.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the toxicity of dioxins, polycyclic aromatic hydrocarbons and related environmental pollutants. Besides drug metabolism, several studies have provided evidence that the AHR and its downstream targets trigger important developmental, physiological and pathophysiological processes. However, in contrast to the molecular mechanisms of AHR-dependent signaling pathways, the transcriptional regulation of the AHR gene itself is as yet only marginally understood.

Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.

Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now.

Role of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expression.

Findings from large epidemiologic studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metalloproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke extracts. Tobacco smoke contains more than 3800 constituents, including numerous water-insoluble polycyclic aromatic hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways.

Aryl hydrocarbon receptor repressor (AhRR) function revisited: repression of CYP1 activity in human skin fibroblasts is not related to AhRR expression.

The skin reacts to environmental noxae by inducing cytochrome P450 (CYP)-catalyzed reactions via activation of the aryl hydrocarbon receptor (AhR). A drawback of this response is the generation of oxidative stress, which is especially dangerous for postreplicative cells such as dermal fibroblasts, in which damage may accumulate over time. Accordingly, in dermal fibroblasts, CYP1 expression is repressed and it has been proposed that this is due to the AhR repressor (AhRR), which is supposedly overexpressed in fibroblasts as compared with other skin cells.

Xenobiotic metabolism capacities of human skin in comparison with a 3D-epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: phase II enzymes.

The 7th Amendment to the EU Cosmetics Directive prohibits the use of animals in cosmetic testing for certain endpoints, such as genotoxicity. Therefore, skin in vitro models have to replace chemical testing in vivo. However, the metabolic competence neither of human skin nor of alternative in vitro models has so far been fully characterized, although skin is the first-pass organ for accidentally or purposely (cosmetics and pharmaceuticals) applied chemicals.

The AhR-Nrf2 pathway in keratinocytes: on the road to chemoprevention?

The ligand-activated transcription factor AhR mediates the cutaneous stress response toward a variety of environmental noxae and is therefore currently of interest for modern preventive medicine. In this issue, Tsuji et al. identify the antifungal agent ketoconazole as an inducer of AhR signaling and the Nrf2 antioxidant response in human keratinocytes.

Epigallocatechin-3-gallate does not affect the activity of enzymes involved in metabolic activation and cellular excretion of benzo[a]pyrene in human colon carcinoma cells.

Benzo[a]pyrene (B[a]P) and related procarcinogens found in cigarette smoke and roasted foodstuff require metabolic activation to build mutagenic DNA adducts that may cause tumor diseases like colorectal cancer. The major B[a]P-activating enzymes belong to the cytochrome-P450 (CYP)-1 family and are regulated by the aryl hydrocarbon receptor (AhR). Previous studies have indicated that an inhibition of AhR is accompanied with a reduced metabolic activation of B[a]P and therefore may act protective against carcinogenesis.

An introduction to the molecular basics of aryl hydrocarbon receptor biology.

Depending on their chemical structure and properties, environmental chemicals and other xenobiotics that enter the cell can affect cellular function by either nonselective binding to cellular macromolecules or by interference with cellular receptors, which would initiate a more defined cell biological response. One of these intracellular chemosensor molecules is the aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family that is known to mediate the biochemical and toxic effects of dioxins, polyaromatic hydrocarbons and related compounds. Numerous investigations have revealed that the AhR is not only a master regulator of drug metabolism activated by anthropogenic chemicals, but is also triggered by natural and endogenous ligands and can influence cell biological endpoints such as growth and differentiation.

Species-specific differential AhR expression protects human neural progenitor cells against developmental neurotoxicity of PAHs.

Background: Because of their lipophilicity, persistent organic pollutants (POPs) cross the human placenta, possibly affecting central nervous system development. Most POPs are known aryl hydrocarbon receptor (AhR) ligands and activators of AhR signaling. Therefore, AhR activation has been suggested to cause developmental neurotoxicity (DNT).

Reactive oxygen species as mediators of membrane-dependent signaling induced by ultrafine particles.

Cell-membrane-dependent proliferative signal transduction activated by ultrafine carbon particles in lung epithelial cells involves the specific induction of Akt and ERK1/2 phosphorylation. Particle-induced generation of reactive oxygen species (ROS) and oxidative stress are regarded as initial molecular mechanisms leading to the induction of diverse cellular responses. Therefore, we aimed to analyze the ROS dependence of the induced activation of the Akt/ERK1/2 signaling pathway upon exposure to ultrafine particulate matter (UPM).

Regulation of dioxin receptor function by different beta-carboline alkaloids.

The dioxin receptor, also known as arylhydrocarbon receptor (AhR), is a ligand-activated transcription factor that mediates the toxicity of dioxins and related environmental contaminants. In addition, there is a growing list of natural compounds, mainly plant polyphenols that can modulate AhR function and downstream signaling with quite unknown consequences for cellular function. We investigate the potential of four different beta-carboline alkaloids to stimulate AhR signaling in human hepatoma cells and keratinocytes.

Luteolin enhances the bioavailability of benzo(a)pyrene in human colon carcinoma cells.

We investigated the effect of luteolin, a plant-derived flavonoid, on benzo(a)pyrene (B(a)P)-stimulated drug metabolism and transport in human colon carcinoma cells. While luteolin treatment inhibited B(a)P-induced expression and activity of arylhydrocarbon receptor-dependent cytochrome P450 enzymes, the overall activity of UDP-glucuronosyltransferases and sulfotransferases was not affected by luteolin, indicating that luteolin affects phase-I but not phase-II function. Luteolin exposure decreased apical transport of B(a)P metabolites due to its interaction with the transporter breast cancer resistance protein.

Polybrominated diphenyl ethers induce developmental neurotoxicity in a human in vitro model: evidence for endocrine disruption.

Background: Polybrominated diphenyl ethers (PBDEs) are persistent and bioaccumulative flame retardants, which are found in rising concentrations in human tissues. They are of concern for human health because animal studies have shown that they possess the potential to be developmentally neurotoxic.

Objective: Because there is little knowledge of the effects of PBDEs on human brain cells, we investigated their toxic potential for human neural development in vitro.

Human neurospheres as three-dimensional cellular systems for developmental neurotoxicity testing.

Background: Developmental neurotoxicity (DNT) of environmental chemicals is a serious threat to human health. Current DNT testing guidelines propose investigations in rodents, which require large numbers of animals. With regard to the "3 Rs" (reduction, replacement, and refinement) of animal testing and the European regulation of chemicals [Registration, Evaluation, and Authorisation of Chemicals (REACH)], alternative testing strategies are needed in order to refine and reduce animal experiments and allow faster and less expensive screening.

The compatible solute ectoine protects against nanoparticle-induced neutrophilic lung inflammation.

Rationale: Inflammatory reactions of the airways induced by nanoparticles of occupational and environmental origin contribute to organ-specific and systemic human diseases. Because this kind of exposure in modern societies is often unavoidable, a strategy of molecular prevention on an individual level could help to prevent inflammation-derived secondary diseases.

Objectives: To test whether the compatible solute ectoine [(S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid], which is known to reduce cell stress effects on a molecular level, prevents nanoparticle-induced lung inflammation.

Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant, which causes a variety of severe health effects, e.g. immunosuppression, hepatotoxicity, and carcinogenesis.

Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair.

Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls.

Statistical methods for detecting genetic interactions: a head and neck squamous-cell cancer study.

Tobacco smoke and occupational exposures to chemicals such as polycyclic aromatic hydrocarbons (PAHs) are, aside from alcohol, the major risk factors for development of head and neck squamous-cell cancer (HNSCC). In this study, new statistical methods were applied. We employ new statistical methods to detect genetic interactions perhaps of higher order, that might play a role in developing HNSCC.

Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation.

Treatment of lung epithelial cells with different kinds of nano-sized particles leads to cell proliferation. Because bigger particles fail to induce this reaction, it is suggested that the special surface properties, due to the extremely small size of these kinds of materials, is the common principle responsible for this specific cell reaction. Here the activation of the protein kinase B (Akt) signaling cascade by carbon nanoparticles was investigated with regard to its relevance for proliferation.

Analysis of the transcriptional regulation and molecular function of the aryl hydrocarbon receptor repressor in human cell lines.

The aryl hydrocarbon receptor repressor (AhRR) is a member of the aryl hydrocarbon receptor (AhR) signaling cascade, which mediates dioxin toxicity and is involved in regulation of cell growth and differentiation. The AhRR was described as a feedback modulator, which counteracts AhR-dependent gene expression. We investigated the molecular mechanisms of transcriptional regulation of the human AhRR by cloning its regulatory DNA region located in intron I of the AhRR.

Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.

UVB radiation-induced signaling in mammalian cells involves two major pathways: one that is initiated through the generation of DNA photoproducts in the nucleus and a second one that occurs independently of DNA damage and is characterized by cell surface receptor activation. The chromophore for the latter one has been unknown. Here, we report that the UVB response involves tryptophan as a chromophore.

ERK-dependent and -independent pathways trigger human neural progenitor cell migration.

Besides differentiation and apoptosis, cell migration is a basic process in brain development in which neural cells migrate several centimeters within the developing brain before reaching their proper positions and forming the right connections. For identifying signaling events that control neural migration and are therefore potential targets of chemicals to disturb normal brain development, we developed a human neurosphere-based migration assay based on normal human neural progenitor (NHNP) cells, in which the distance is measured that cells wander over time. Applying this assay, we investigated the role of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the regulation of NHNP cell migration.

The arylhydrocarbon receptor repressor (AhRR): structure, expression, and function.

The arylhydrocarbon receptor (AhR) pathway is known to be critical for cellular events, especially for those evoked by several environmental chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Whereas the function of the AhR in TCDD toxicity is well analyzed, the importance of the recently cloned AhRR in the TCDD-stimulated AhR signaling cascade is still unclear. In mammalian tissues, the AhRR gene seems to be ubiquitously expressed and its expression is altered by various AhR ligands.

Concepts in molecular dermatotoxicology.

In the recent years, molecular research has successfully elucidated some of the major mechanisms through which environmental noxae damage human skin. From this knowledge, novel concepts for skin protection have been developed. Here, we provide a brief overview of some of the most exciting and intriguing concepts in molecular dermatotoxicology.