scholarly journals The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases

2018 ◽  
Vol 19 (12) ◽  
pp. 3851 ◽  
Author(s):  
Drew Neavin ◽  
Duan Liu ◽  
Balmiki Ray ◽  
Richard Weinshilboum
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptor ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Inflammatory Processes ◽  
Targeted Gene Expression

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

scholarly journals The Role of the Aryl Hydrocarbon Receptor (AhR) in the Immune Response against Microbial Infections

2021 ◽  
Author(s):  
Lixing Huang ◽  
Rongchao He ◽  
Youyu Zhang ◽  
Qingpi Yan
Keyword(s):  
Immune Response ◽  
Aryl Hydrocarbon Receptor ◽  
Nuclear Receptor ◽  
Cellular Response ◽  
Inflammatory Responses ◽  
Environmental Stressors ◽  
Aryl Hydrocarbon ◽  
Microbial Infections

Aryl hydrocarbon receptor (AhR), an important nuclear receptor, regulates the cellular response to environmental stressors. It is well known for its critical functions in toxicology, but is currently considered an essential regulator of diseases, with specific modulatory effects on immune, antimicrobial and inflammatory responses. The present chapter discusses AhR’s function and mechanism in the immune response against microbial infections.

scholarly journals Mutant glucocorticoid receptor binding elements on the interleukin-6 promoter regulate dexamethasone effects

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wen-Teng Chang ◽  
Ming-Yuan Hong ◽  
Chien-Liang Chen ◽  
Chi-Yuan Hwang ◽  
Cheng-Chieh Tsai ◽  
...  
Keyword(s):  
Binding Sites ◽  
Inflammatory Diseases ◽  
Inducible Promoter ◽  
Transcriptional Factor ◽  
Factor Binding ◽  
Inflammatory Processes ◽  
Nuclear Receptor Family ◽  
Specificity Protein ◽  
Receptor Family ◽  
Pro Inflammatory Cytokines

Abstract Background Glucocorticoids (GCs) have been extensively used as essential modulators in clinical infectious and inflammatory diseases. The GC receptor (GR) is a transcription factor belonging to the nuclear receptor family that regulates anti-inflammatory processes and releases pro-inflammatory cytokines, such as interleukin (IL)-6. Results Five putative GR binding sites and other transcriptional factor binding sites were identified on theIL-6 promoter, and dexamethasone (DEX) was noted to reduce the lipopolysaccharide (LPS)-induced IL-6 production. Among mutant transcriptional factor binding sites, nuclear factor-kappa B (NF-κB), activator protein (AP)-1, and specificity protein (Sp)1–2 sites reduced basal and LPS-induced IL-6 promoter activities through various responses. The second GR binding site (GR2) was noted to play a crucial role in both basal and inducible promoter activities in LPS-induced inflammation. Conclusions We concluded that selective GR2 modulator might exert agonistic and antagonistic effects and could activate crucial signaling pathways during the LPS-stimulated inflammatory process.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

scholarly journals DNA damage independent inhibition of NF-κB transcription by anthracyclines

2020 ◽  
Author(s):  
Angelo Chora ◽  
Dora Pedroso ◽  
Nadja Pejanovic ◽  
Eleni Kyriakou ◽  
Henrique Colaço ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factors ◽  
Binding Sites ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Anticancer Properties ◽  
Dna Binding Sites ◽  
Immune Mediated ◽  
Life Threatening ◽  
Molecular Patterns

AbstractTranscriptional programs leading to induction of a large number of genes can be rapidly initiated by the activation of only few selected transcription factors. Upon stimulation of macrophages with microbial-associated molecular patterns (MAMPs), the activation of the nuclear factor kappa B (NF-κB) family of transcription factors triggers inflammatory responses that, left uncontrolled, can lead to excessive inflammation with life-threatening consequences for the host. Here we identify and characterize a novel effect of Anthracyclines, a class of drugs currently used as potent anticancer drugs, in the regulation of NF-κB transcriptional activity in BMDMs, in addition to the previously reported DNA damage and histone eviction. Anthracyclines, including Doxorubicin, Daunorubicin and Epirubicin, disturb the complexes formed between the NF-κB subunit RelA and its DNA binding sites, to limit NF-κB-dependent gene transcription during inflammatory responses, including of pivotal pro-inflammatory mediators such as TNF. We observed that suppression of inflammation can also be mediated by Aclarubicin, Doxorubicinone and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other Anthracyclines, but do not induce DNA damage in the tested concentrations. This novel mechanism of action of Anthracyclines, contributing to the reduction of inflammation, is thus independent of the activation of DNA damage responses and may be relevant for the development of novel strategies targeting immune-mediated inflammatory diseases.

13C-caffeine breath test results show high dependence of aryl-hydrocarbon receptor SNPs

2020 ◽  
Author(s):  
Mchiko Ishii ◽  
Yukimoto Ishii ◽  
Tomohisa Nakayama ◽  
Yasuo Takahashi ◽  
Satoshi Asai
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Breath Test ◽  
Smoking Status ◽  
Area Under The Curve ◽  
Black Tea ◽  
Nucleotide Polymorphisms ◽  
Aryl Hydrocarbon ◽  
Significant Difference ◽  
Caffeine Metabolism ◽  
Characteristic Area

Abstract Aim: We investigated the relationship between trimethyl-13C-caffeine breath test (triCBT) and single nucleotide polymorphisms (SNPs) that are related to caffeine metabolism and consumption.Methods: Subjects were 132 young healthy adults (median 21 years: 101 male, 31 female). Subjects completed a questionnaire that enquired about their smoking status, consumption of caffeinated drinks (including coffee, black tea, green tea), height, weight, and body mass index (BMI). DNA was extracted from saliva, and genotyping was performed using TaqMan® SNP Genotyping for cytochrome P4501A2 rs762551, rs2472297, and aryl-hydrocarbon receptor rs4410790. Trimethyl 13C-caffeine (100 mg) was dissolved in distilled water and administered orally. Subsequently, breath samples were collected every 10 mins for 90 mins. Infrared spectroscopy was used to analyze the amount of 13CO2 in the expired breath, and the sum (Δ13CO2) over 90 min (S90m) was calculated.Results: All subjects had genotype CC for rs2472297. S90m was not significantly different among rs762551 genotypes; however, there was a significant difference in S90m among rs4410790 genotypes. Δ13CO2 was significantly affected by rs4410790 SNPs and smoking. The receiver operating characteristic area under the curve was 0.758 when rs4410790 phenotype C was considered positive. When the cutoff value was set to S90m (23.4 ‰), the sensitivity and specificity were 71.4% and 72.1%, respectively.Conclusions: Our results suggest that caffeine demethylation is affected by rs4410790 SNPs and smoking, and that triCBT can be used to identify SNPs in rs4410790.

scholarly journals Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Christopher Platen ◽  
Stephan Dreschers ◽  
Jessica Wappler ◽  
Andreas Ludwig ◽  
Stefan Düsterhöft ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Infections ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Intrinsic Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

scholarly journals Galactomyces fermentation filtrate prevents T helper 2‐mediated reduction of filaggrin in an aryl hydrocarbon receptor‐dependent manner

2015 ◽  
Vol 40 (7) ◽  
pp. 786-793 ◽  
Author(s):  
K. Takei ◽  
C. Mitoma ◽  
A. Hashimoto‐Hachiya ◽  
M. Takahara ◽  
G. Tsuji ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Dependent Manner ◽  
T Helper ◽  
T Helper 2 ◽  
Aryl Hydrocarbon ◽  
Mediated Reduction

scholarly journals Inhibition of two-pore channels in antigen-presenting cells promotes the expansion of TNFR2-expressing CD4+Foxp3+ regulatory T cells

2020 ◽  
Vol 6 (40) ◽  
pp. eaba6584
Author(s):  
Tianzhen He ◽  
De Yang ◽  
Xiao-Qing Li ◽  
Mengmeng Jiang ◽  
Md Sahidul Islam ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Antigen Presenting Cells ◽  
Surface Expression ◽  
Pore Channel ◽  
Dependent Manner ◽  
Antigen Presenting

CD4+Foxp3+ regulatory T cells (Tregs) are pivotal for the inhibition of autoimmune inflammatory responses. One way to therapeutically harness the immunosuppressive actions of Tregs is to stimulate the proliferative expansion of TNFR2-expressing CD4+Foxp3+ Tregs via transmembrane TNF (tmTNF). Here, we report that two-pore channel (TPC) inhibitors markedly enhance tmTNF expression on antigen-presenting cells. Furthermore, injection of TPC inhibitors including tetrandrine, or TPC-specific siRNAs in mice, increases the number of Tregs in a tmTNF/TNFR2-dependent manner. In a mouse colitis model, inhibition of TPCs by tetrandrine markedly attenuates colon inflammation by expansion of Tregs. Mechanistically, we show that TPC inhibitors enhance tmTNF levels by disrupting surface expression of TNF-α–converting enzyme by regulating vesicle trafficking. These results suggest that the therapeutic potential of TPC inhibitors is mediated by expansion of TNFR2-expressing Tregs and elucidate the basis of clinical use in the treatment of autoimmune and other inflammatory diseases.

scholarly journals A Protective Role of Aryl Hydrocarbon Receptor Repressor in Inflammation and Tumor Growth

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 589 ◽  
Author(s):  
Christoph F. A. Vogel ◽  
Yasuhiro Ishihara ◽  
Claire E. Campbell ◽  
Sarah Y. Kado ◽  
Aimy Nguyen-Chi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Aryl Hydrocarbon Receptor ◽  
Inflammatory Responses ◽  
Environmental Pollutants ◽  
Protective Role ◽  
Potential Therapeutic Target ◽  
Embryonic Fibroblasts ◽  
Aryl Hydrocarbon ◽  
Enhancer Binding Protein

The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds, and is associated with the promotion of various malignancies, including lymphoma. The aryl hydrocarbon receptor repressor (AhRR), a ligand-independent, transcriptionally inactive AhR-like protein is known to repress AhR signaling through its ability to compete with the AhR for dimerization with the AhR nuclear translocator (ARNT). While AhRR effectively blocks AhR signaling, several aspects of the mechanism of AhRR’s functions are poorly understood, including suppression of inflammatory responses and its putative role as a tumor suppressor. In a transgenic mouse that overexpresses AhRR (AhRR Tg) we discovered that these mice suppress 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)- and inflammation-induced tumor growth after subcutaneous challenge of EL4 lymphoma cells. Using mouse embryonic fibroblasts (MEF) we found that AhRR overexpression suppresses the AhR-mediated anti-apoptotic response. The AhRR-mediated inhibition of apoptotic resistance was associated with a suppressed expression of interleukin (IL)-1β and cyclooxygenase (COX)-2, which was dependent on activation of protein kinase A (PKA) and the CAAT-enhancer-binding protein beta (C/EBPβ). These results provide mechanistic insights into the role of the AhRR to suppress inflammation and highlight the AhRR as a potential therapeutic target to suppress tumor growth.

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