scholarly journals Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

2019 ◽  
Vol 33 (10) ◽  
pp. 10844-10858 ◽  
Author(s):  
Hee Young Kim ◽  
Tae-Hyun Yoo ◽  
Joo-Youn Cho ◽  
Hyeon Chang Kim ◽  
Won-Woo Lee
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Indoxyl Sulfate ◽  
Human Macrophages ◽  
Aryl Hydrocarbon ◽  
Tnf Α

scholarly journals Crucial Role of the Aryl Hydrocarbon Receptor (AhR) in Indoxyl Sulfate-Induced Vascular Inflammation

2016 ◽  
Vol 23 (8) ◽  
pp. 960-975 ◽  
Author(s):  
Shunsuke Ito ◽  
Mizuko Osaka ◽  
Takeo Edamatsu ◽  
Yoshiharu Itoh ◽  
Masayuki Yoshida
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Crucial Role ◽  
Vascular Inflammation ◽  
Indoxyl Sulfate ◽  
Aryl Hydrocarbon

scholarly journals Aryl Hydrocarbon Receptor Modulates the Expression of TNF-α and IL-8 in Human Sebocytes via the MyD88-p65NF-κB/p38MAPK Signaling Pathways

2018 ◽  
Vol 11 (1) ◽  
pp. 41-51 ◽  
Author(s):  
Xiao-Xiao Hou ◽  
Guangjie Chen ◽  
Amir M. Hossini ◽  
Tingting Hu ◽  
Lanqi Wang ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Physiological Stress ◽  
Acne Vulgaris ◽  
Receptor Protein ◽  
Inflammatory Factors ◽  
Induced Expression ◽  
Aryl Hydrocarbon ◽  
Tnf Α ◽  
P38mapk Signaling ◽  
Myeloid Differentiation Factor

Activation of Toll-like receptor (TLR)-2 and subsequent inflammatory response contribute to lesion development in acne vulgaris. A cross-talk between aryl hydrocarbon receptor (AhR), a cytosolic receptor protein that responds to environmental and physiological stress, and TLRs has recently been reported. In this study, we explored the possible role of AhR in the effects induced on cultured human SZ95 sebocytes by peptidoglycan (PGN), a classic TLR2 agonist. PGN-induced secretion of inflammatory factors TNF-α and IL-8 in human SZ95 sebocytes was suppressed after knockdown of AhR and pretreatment with the AhR antagonist CH223191. In addition, the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhanced TNF-α and IL-8 secretion in PGN-pretreated sebocytes. Furthermore, PGN-induced expression of myeloid differentiation factor 88 (MyD88), phospho-p38MAPK (p-p38MAPK), and p-p65NF-κB was strengthened by TCDD and repressed by CH223191. AhR inhibition by transfecting shRNA blocked the ability of PGN to stimulate phosphorylation of p38MAPK and p65NF-κB in SZ95 sebocytes. Overall, these data demonstrate that AhR is able to modulate PGN-induced expression of TNF-α and IL-8 in human SZ95 sebocytes involving the MyD88-p65NF-κB/p38MAPK signaling pathway, which probably indicates a new mechanism in TLR2-mediated acne.

scholarly journals Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection

2014 ◽  
Vol 82 (8) ◽  
pp. 3127-3140 ◽  
Author(s):  
Fatima Brant ◽  
Aline S. Miranda ◽  
Lisia Esper ◽  
David Henrique Rodrigues ◽  
Lucas Miranda Kangussu ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Plasmodium Berghei ◽  
Transforming Growth Factor ◽  
Interleukin 17 ◽  
High Morbidity ◽  
Content Type ◽  
Aryl Hydrocarbon ◽  
Tnf Α ◽  
Ifn Γ ◽  
The Brain

ABSTRACTInfection withPlasmodium falciparummay result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality.Plasmodium bergheiAnka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected withP. bergheiAnka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, andP. bergheiAnka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.

The Uremic Toxin Indoxyl Sulfate Impairs Angiogenesis Through Aryl Hydrocarbon Receptor Activation

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Zachary R. Salyers ◽  
Trace Thome ◽  
Madeline Coleman ◽  
Terence Ryan
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Indoxyl Sulfate ◽  
Uremic Toxin ◽  
Aryl Hydrocarbon

scholarly journals Role of Resveratrol on Indoxyl Sulfate-Induced Endothelial Hyperpermeability via Aryl Hydrocarbon Receptor (AHR)/Src-Dependent Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Eskedar Getachew Assefa ◽  
Qiaoqiao Yan ◽  
Siameregn Berhe Gezahegn ◽  
Maibouge Tanko Mahamane Salissou ◽  
Shuiqing He ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Src Kinase ◽  
Endothelial Permeability ◽  
High Serum ◽  
Indoxyl Sulfate ◽  
Dietary Polyphenols ◽  
Aryl Hydrocarbon ◽  
Dependent Pathway ◽  
Endothelial Hyperpermeability

Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.

scholarly journals Activation of aryl hydrocarbon receptor mediates suppression of hypoxia-inducible factor-dependent erythropoietin expression by indoxyl sulfate

2016 ◽  
Vol 310 (2) ◽  
pp. C142-C150 ◽  
Author(s):  
Hirobumi Asai ◽  
Junya Hirata ◽  
Ayumi Hirano ◽  
Kazuya Hirai ◽  
Sayaka Seki ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Mrna Expression ◽  
Transcriptional Activation ◽  
Hypoxia Inducible Factor ◽  
Indoxyl Sulfate ◽  
Renal Anemia ◽  
Nuclear Accumulation ◽  
Blood Levels ◽  
Uremic Toxin ◽  
Aryl Hydrocarbon

Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood of patients with chronic kidney disease (CKD). In addition to the involvement in the progression of CKD, a recent report indicates that IS suppresses hypoxia-inducible factor (HIF)-dependent erythropoietin (EPO) production, suggesting that IS may also contribute to the progression of renal anemia. In this report, we provide evidence that aryl hydrocarbon receptor (AhR) mediates IS-induced suppression of HIF activation and subsequent EPO production. In HepG2 cells, IS at concentrations similar to the blood levels in CKD patients suppressed hypoxia- or cobalt chloride-induced EPO mRNA expression and transcriptional activation of HIF. IS also induced AhR activation, and AhR blockade resulted in abolishment of IS-induced suppression of HIF activation. The HIF transcription factor is a heterodimeric complex composed of HIF-α subunits (HIF-1α and HIF-2α) and AhR nuclear translocator (ARNT). IS suppressed nuclear accumulation of the HIF-α-ARNT complex accompanied by an increase of the AhR-ARNT complex in the nucleus, implying the involvement of interactions among AhR, HIF-α, and ARNT in the suppression mechanism. In rats, oral administration of indole, a metabolic precursor of IS, inhibited bleeding-induced elevation of renal EPO mRNA expression and plasma EPO concentration and strongly induced AhR activation in the liver and renal cortex tissues. Collectively, this study is the first to elucidate the detailed mechanism by which AhR plays an indispensable role in the suppression of HIF activation by IS. Hence, IS-induced activation of AhR may be a potential therapeutic target for treating renal anemia.

scholarly journals Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

2020 ◽  
Vol 21 (10) ◽  
pp. 3486 ◽  
Author(s):  
Wen-Chih Liu ◽  
Jia-Fwu Shyu ◽  
Paik Seong Lim ◽  
Te-Chao Fang ◽  
Chien-Lin Lu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Critical Role ◽  
Osteoclast Differentiation ◽  
Indoxyl Sulfate ◽  
Raw 264.7 Cells ◽  
High Dose ◽  
Activated T Cells ◽  
Aryl Hydrocarbon

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.

scholarly journals Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells

2015 ◽  
Vol 30 (10) ◽  
pp. 1683-1692 ◽  
Author(s):  
Akinobu Ochi ◽  
Katsuhito Mori ◽  
Shinya Nakatani ◽  
Masanori Emoto ◽  
Tomoaki Morioka ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Hepg2 Cells ◽  
Indoxyl Sulfate ◽  
Fetuin A ◽  
Aryl Hydrocarbon
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