Cell-Specific Regulation of Human Aryl Hydrocarbon Receptor Expression by Transforming Growth Factor-β1

2001 ◽  
Vol 59 (4) ◽  
pp. 716-724 ◽  
Author(s):  
Sandra Wolff ◽  
Patricia A. Harper ◽  
Judy M. Y. Wong ◽  
Volker Mostert ◽  
Yanping Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Receptor Expression ◽  
Aryl Hydrocarbon ◽  
Specific Regulation

scholarly journals Ligand-Independent Regulation of Transforming Growth Factor β1 Expression and Cell Cycle Progression by the Aryl Hydrocarbon Receptor

2007 ◽  
Vol 27 (17) ◽  
pp. 6127-6139 ◽  
Author(s):  
Xiaoqing Chang ◽  
Yunxia Fan ◽  
Saikumar Karyala ◽  
Sandy Schwemberger ◽  
Craig R. Tomlinson ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Transforming Growth Factor Β1 ◽  
Cyclin Dependent Kinase ◽  
Aryl Hydrocarbon ◽  
Tgf Β1

ABSTRACT The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the toxic effects of its xenobiotic ligands and acts as an environmental checkpoint during the cell cycle. We expressed stably integrated, Tet-Off-regulated AHR variants in fibroblasts from AHR-null mice to further investigate the AHR role in cell cycle regulation. Ahr +/+ fibroblasts proliferated significantly faster than Ahr − / − fibroblasts did, and exposure to a prototypical AHR ligand or deletion of the ligand-binding domain did not change their proliferation rates, indicating that the AHR function in cell cycle was ligand independent. Growth-promoting genes, such as cyclin and cyclin-dependent kinase genes, were significantly down-regulated in Ahr − / − cells, whereas growth-arresting genes, such as the transforming growth factor β1 (TGF-β1) gene, extracellular matrix (ECM)-related genes, and cyclin-dependent kinase inhibitor genes, were up-regulated. Ahr − / − fibroblasts secreted significantly more TGF-β1 into the culture medium than Ahr +/+ fibroblasts did, and Ahr − / − showed increased levels of activated Smad4 and TGF-β1 mRNA. Inhibition of TGF-β1 signaling by overexpression of Smad7 reversed the proliferative and gene expression phenotype of Ahr − / − fibroblasts. Changes in TGF-β1 mRNA accumulation were due to stabilization resulting from decreased activity of TTP, the tristetraprolin RNA-binding protein responsible for mRNA destabilization through AU-rich motifs. These results show that the Ah receptor possesses interconnected intrinsic cellular functions, such as ECM formation, cell cycle control, and TGF-β1 regulation, that are independent of activation by either exogenous or endogenous ligands and that may play a crucial role during tumorigenesis.

scholarly journals The Aryl Hydrocarbon Receptor–Dependent TGF-α/VEGF-B Ratio Correlates With Disease Subtype and Prognosis in Multiple Sclerosis

2021 ◽  
Vol 8 (5) ◽  
pp. e1043
Author(s):  
Ana Cirac ◽  
Thanos Tsaktanis ◽  
Tobias Beyer ◽  
Mathias Linnerbauer ◽  
Till Andlauer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Growth Factor ◽  
Disease Activity ◽  
Aryl Hydrocarbon Receptor ◽  
Transforming Growth Factor ◽  
Class Iii ◽  
Cns Inflammation ◽  
Aryl Hydrocarbon ◽  
Potential Marker ◽  
Agonistic Activity

ObjectiveTo evaluate the aryl hydrocarbon receptor (AHR)-dependent transforming growth factor alpha (TGF-α)/vascular endothelial growth factor B (VEGF-B) ratio, which regulates the effects of metabolic, dietary, and microbial factors on acute and chronic CNS inflammation, as a potential marker in multiple sclerosis (MS).MethodsTGF-α, VEGF-B, and AHR agonistic activity were determined in serum of 252 patients with relapsing-remitting (RR) MS, primary and secondary progressive MS, as well as during active disease (clinically isolated syndrome [CIS] and RRMS relapse).ResultsThe TGF-α/VEGF-B ratio and AHR agonistic activity were decreased in all MS subgroups with a stable disease course as compared to controls. During active CNS inflammation in CIS and RRMS relapse, the TGF-α/VEGF-B ratio and AHR agonistic activity were increased. Conversely, in patients with minimal clinical impairment despite long-standing disease, the TGF-α/VEGF-B ratio and AHR agonistic activity were unaltered. Finally, the TGF-α/VEGF-B ratio and AHR agonistic activity correlated with neurologic impairment and time to conversion from CIS to MS.ConclusionsThe AHR-dependent TGF-α/VEGF-B ratio is altered in a subtype, severity, and disease activity–specific manner and correlates with time to conversion from CIS to MS. It may thus represent a novel marker and serve as additive guideline for immunomodulatory strategies in MS.Classification of EvidenceThis study provides Class III evidence that serum levels of AHR, TGF-α, and VEGF-B distinguish subtypes of MS and predict the severity and disease activity of MS.

scholarly journals Inhibition of Aryl Hydrocarbon Receptor Attenuates Hyperglycemia‐Induced Hematoma Expansion in an Intracerebral Hemorrhage Mouse Model

2021 ◽  
Author(s):  
Reng Ren ◽  
Qin Lu ◽  
Prativa Sherchan ◽  
Yuanjian Fang ◽  
Cameron Lenahan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Aryl Hydrocarbon Receptor ◽  
Transforming Growth Factor ◽  
Hematoma Expansion ◽  
Clinical Prognosis ◽  
Aryl Hydrocarbon

Background Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia‐induced blood–brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia‐induced HE in a male mouse model of ICH. Methods and Results CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2′,4′‐trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3‐methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin‐1/transforming growth factor‐β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB‐related proteins, ZO‐1 and Claudin‐5. Conclusions AHR may serve as a potential therapeutic target to attenuate hyperglycemia‐induced hematoma expansion and to preserve the BBB in patients with ICH.

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