Endogenous and Exogenous Ligands of Aryl Hydrocarbon Receptor: Current State of Art

Abstract While activation of the aryl hydrocarbon receptor (AhR) by exogenous ligands is well investigated, its physiological function is less understood. By extending research in AhR biology, evidence appeared that the receptor generally plays an important role in cell physiology. In keratinocytes, little is known about endogenous functions of the AhR. In order to expand this knowledge, we analyzed the impact of AhR knockdown on cell cycle progression in HaCaT cells and showed that proliferation of siAhR HaCaT cells was significantly decreased. In line with that result, western blot analysis revealed that protein level of the cyclin dependent kinase inhibitor p27KIP1 was increased, whereas protein level of the cyclin dependent kinase (CDK) 2 was reduced. CDK4 and CDK6 protein levels remained unchanged, whereas protein level of the retinoblastoma protein (pRB) was reduced. By measuring ethoxyresorufin-O-deethylase (EROD) activity we showed that endogenous cytochrome P450 1 (CYP1), especially CYP1A1 is required for normal cell cycle in HaCaT cells, as well. To the best of our knowledge, we provide evidence for the first time in human skin cells, that in the absence of exogenous ligands, the AhR promotes cell cycle progression in HaCaT cells and one can speculate that this is the physiological function of this receptor in keratinocytes.

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Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases

Nutrients ◽

10.3390/nu12092846 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2846 ◽

Cited By ~ 1

Author(s):

Mohammed Ghiboub ◽

Charlotte M. Verburgt ◽

Bruno Sovran ◽

Marc A. Benninga ◽

Wouter J. de Jonge ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Human Health ◽

Metabolic Disorders ◽

Nuclear Protein ◽

Nutritional Therapy ◽

Aryl Hydrocarbon ◽

Health And Disease ◽

Exogenous Ligands ◽

Signaling Activation ◽

Therapeutic Perspective

The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities.

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The Aryl Hydrocarbon Receptor in Asthma: Friend or Foe?

International Journal of Molecular Sciences ◽

10.3390/ijms21228797 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8797

Author(s):

Odile Poulain-Godefroy ◽

Mélodie Bouté ◽

Julie Carrard ◽

Daniel Alvarez-Simon ◽

Anne Tsicopoulos ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Asthmatic Patients ◽

Aryl Hydrocarbon ◽

Important Player ◽

Polycyclic Aromatic ◽

Exogenous Ligands ◽

Anti Inflammatory ◽

Antigen Presenting ◽

Two Sides

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has emerged as an important player in asthma control. AhR is responsive to environmental molecules and endogenous or dietary metabolites and regulates innate and adaptive immune responses. Binding of this receptor by different ligands has led to seemingly opposite responses in different asthma models. In this review, we present two sides of the same coin, with the beneficial and deleterious roles of AhR evaluated using known endogenous or exogenous ligands, deficient mice or antagonists. On one hand, AhR has an anti-inflammatory role since its activation in dendritic cells blocks the generation of pro-inflammatory T cells or shifts macrophages toward an anti-inflammatory M2 phenotype. On the other hand, AhR activation by particle-associated polycyclic aromatic hydrocarbons from the environment is pro-inflammatory, inducing mucus hypersecretion, airway remodelling, dysregulation of antigen presenting cells and exacerbates asthma features. Data concerning the role of AhR in cells from asthmatic patients are also reviewed, since AhR could represent a potential target for therapeutic immunomodulation.

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The Role of Aryl-Hydrocarbon Receptor (AhR) in Osteoclast Differentiation and Function

Cells ◽

10.3390/cells9102294 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2294

Author(s):

Robin Park ◽

Shreya Madhavaram ◽

Jong Dae Ji

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Osteoclast Differentiation ◽

Environmental Pollutants ◽

Endogenous Ligand ◽

Aryl Hydrocarbon ◽

Binding Time ◽

Functional Regulation ◽

Exogenous Ligands ◽

And Function

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays a crucial role in bone remodeling through altering the interplay between bone-forming osteoblasts and bone-resorbing osteoclasts. While effects of AhR signaling in osteoblasts are well understood, the role and mechanism of AhR signaling in regulating osteoclastogenesis is not widely understood. AhR, when binding with exogenous ligands (environmental pollutants such as polycylic aryl hydrocarbon (PAH), dioxins) or endogenous ligand indoxyl-sulfate (IS), has dual functions that are mediated by the nature of the binding ligand, binding time, and specific pathways of distinct ligands. In this review, AhR is discussed with a focus on (i) the role of AhR in osteoclast differentiation and function and (ii) the mechanisms of AhR signaling in inhibiting or promoting osteoclastogenesis. These findings facilitate an understanding of the role of AhR in the functional regulation of osteoclasts and in osteoclast-induced bone destructive conditions such as rheumatoid arthritis and cancer.

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