The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism

Kung, Tiffany S.; Murphy, Kyle; White, Lori A.

doi:10.1016/j.bcp.2008.09.031

Cited by 81 publications

(54 citation statements)

References 103 publications

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“…These results demonstrated that lower expression of AhR might be involved in the mechanisms of CRSwNPwAR. Data showed that AhR signaling played an important role in the regulation of tissue and matrix remodeling through activating some identified targets, and activation of the AhR pathway resulted in the increased expression of collagens [24]. The details of the mechanisms of AhR in the remodeling of CRSwNP require further research.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of the Aryl Hydrocarbon Receptor and Transforming Growth Factor Beta 1 in Chronic Rhinosinusitis with Nasal Polyps with Allergic Rhinitis

Chen

Xiao²,

Liu³

et al. 2017

ORL

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Objective: This study aimed to determine the aryl hydrocarbon receptor (AhR) and transforming growth factor beta 1 (TGF-β1) expression levels in chronic rhinosinusitis (CRS) and their possible correlation with allergic state and tissue remodeling. Methods: Patients were enrolled and divided into the following groups: CRS without nasal polyps (NP) without allergic rhinitis (AR) (CRSsNPsAR; n = 20), CRS with NP with AR (CRSwNPwAR; n = 20), CRS with NP without AR (CRSwNPsAR; n = 20), and controls (n = 15). Tissue samples were analyzed by Masson trichrome staining for collagen, while the location and expression of AhR and TGF-β1 were analyzed by immunohistochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blotting. Results: The collagen amounts as well as AhR and TGF-β1 mRNA and protein expression levels were significantly increased in the CRSsNPsAR group compared with the CRSwNP (CRSwNPsAR and CRSwNPwAR) samples (p < 0.01). However, higher collagen amounts (p < 0.05) and higher TGF-β1 (p < 0.05) but lower AhR expression levels (p < 0.05) were detected in the CRSwNPwAR versus the CRSwNPsAR patients. Both AhR and TGF-β1 expression were positively correlated with the collagen level in CRS samples (p < 0.01). Conclusions: Elevated AhR expression may be involved in the progression of tissue remodeling in CRSsNPsAR similar to TGF-β1 expression. Conversely, lower AhR expression may be involved in allergic reactions in CRSwNPwAR.

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Section: Discussionmentioning

confidence: 99%

Differential Expression of the Aryl Hydrocarbon Receptor and Transforming Growth Factor Beta 1 in Chronic Rhinosinusitis with Nasal Polyps with Allergic Rhinitis

Chen

Xiao²,

Liu³

et al. 2017

ORL

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“…Studies on the mechanisms of AhR have mainly used the HAH 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as the prototype ligand, which is resistant to environmental and biological degradation (14). Upon ligand binding, the PAS domain of the AhR heterodimerizes with a structurally related protein called the AhR nuclear translocator (ARNT).…”

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confidence: 99%

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Hu¹,

Herrmann²,

Bednar³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

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The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR −/− mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR −/− mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.retinal pigment epithelium | retinal disease | toxin metabolism | oxidized low density lipoprotein A ge-related macular degeneration (AMD) is the leading cause of vision loss in individuals over the age of 55 y in the Western world (1). It is a complex and heterogeneous disease, multifactorial with genetic, systemic health, and environmental factors regulating its initiation and progression (2, 3). Phenotypically, eyes with the dry clinical subtype are characterized by accumulation of focal and diffuse extracellular lipid protein-rich deposits below the retinal pigment epithelial cells (sub-RPE in 85-87% of cases) and/or within Bruch's membrane. These deposits include drusen, basal laminar, and basal linear deposits (4, 5) and are associated with RPE dysfunction, apoptosis, and ultimately degeneration. The latter of which, RPE atrophy and degeneration, is seen in an advanced form of dry AMD called geographic atrophy. Currently, there are no treatment options available for these patients. Despite advances in our understanding of the composition of sub-RPE deposits (6-8), the critical molecular events and signaling pathways leading to progressive RPE dysfunction and extracellular deposit biogenesis are still unknown.

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“…The TGF-β pathway, in turn, is controlled by the activity of αv integrins in glioma cells (11). AhR has been described as a regulator of the composition of integrins at the cell surface (13,(20)(21)(22)(23), but inhibitory effects of AhR on FAK phosphorylation, a central mediator of integrin signaling, have also been observed (14,24). These findings provided the rationale for the present study, which aimed at elucidating a possible link between the AhR and integrin signaling pathways in modulating the activity of the TGF-β pathway in glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, certain integrins are overexpressed in tumor cells as well as tumor-associated host cells and may have a profound role in tumor progression (12). AhR in turn may regulate the composition of integrin receptors on the cell surface and signaling of focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase involved in integrin signaling cascades (5,13,14). Here, we aimed at defining a possible interplay of integrins and AhR in the regulation of TGF-β signaling in glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

The aryl hydrocarbon receptor links integrin signaling to the TGF-β pathway

et al. 2015

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Glioblastoma is the most common and aggressive form of intrinsic brain tumor. Transforming growth factor (TGF)-represents a central mediator of the malignant phenotype of these tumors by promoting invasiveness and angiogenesis, maintaining tumor cell stemness and inducing profound immunosuppression. Integrins, which are highly expressed in glioma cells, interact with the TGF-pathway. Furthermore, a link has been described between activity of the transcription factor aryl hydrocarbon receptor (AhR) and TGF-expression. Here we demonstrate that integrin inhibition, using v, 3 or 5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological inhibition by the cyclic RGD peptide EMD 121974 (cilengitide) or the non-peptidic molecule GLPG0187, inhibits AhR activity. These effects are independent of cell detachment or cell density. While AhR mRNA expression was not affected by integrin inhibition, AhR total and nuclear protein levels were reduced, suggesting that integrin inhibition-mediated regulation of AhR may occur at a post-transcriptional level. AhR-null astrocytes, AhR-null hepatocytes or glioblastoma cells with a transiently silenced AhR gene showed reduced sensitivity to integrin inhibition-mediated alterations in TGF-signaling, indicating that AhR mediates integrin control of the TGF-pathway. Accordingly, there was a significant correlation of v integrin levels with nuclear AhR and pSmad2 levels as determined by immunohistochemistry in human glioblastoma in vivo. In summary, this study identifies a signaling network comprising integrins, AhR and TGF-and validates integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block AhR-and TGF--controlled features of malignancy in human glioblastoma. Here we demonstrate that integrin inhibition, using αv, β3 or β5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological inhibition by the cyclic RGD peptide EMD 121974 (cilengitide) or the non-peptidic molecule GLPG0187, inhibits AhR activity.These effects are independent of cell detachment or cell density. While AhR mRNA expression was not affected by integrin inhibition, AhR total and nuclear protein levels were reduced, suggesting that integrin inhibition-mediated regulation of AhR may occur at a posttranscriptional level. AhR-null astrocytes, AhR-null hepatocytes, or glioblastoma cells with a transiently silenced AhR gene showed reduced sensitivity to integrin inhibition-mediated alterations in TGF-β signaling indicating that AhR mediates integrin control of the TGF-β pathway. Accordingly, there was a significant correlation of αv integrin levels with nuclear AhR and pSmad2 levels as determined by immunohistochemistry in human glioblastoma in vivo.In summary, this study identifies a signaling network comprising integrins, AhR and TGF-β and validates integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block AhR-and TGF--controlled features of malignancy in human glio...

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The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism

Cited by 81 publications

References 103 publications

Differential Expression of the Aryl Hydrocarbon Receptor and Transforming Growth Factor Beta 1 in Chronic Rhinosinusitis with Nasal Polyps with Allergic Rhinitis

Differential Expression of the Aryl Hydrocarbon Receptor and Transforming Growth Factor Beta 1 in Chronic Rhinosinusitis with Nasal Polyps with Allergic Rhinitis

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

The aryl hydrocarbon receptor links integrin signaling to the TGF-β pathway

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