A putative role for the aryl hydrocarbon receptor (AHR) gene in a patient with cyclical Cushing’s disease

Staphylococcus (S.) aureus is an important pathogen causing various infections including - as most frequently isolated bacterium - cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to S. aureus by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of S. aureus, the mechanisms underlying the interplay between S. aureus and keratinocytes are still emerging. Here we report that S. aureus induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by S. aureus was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) < 2 kDa secreted by S. aureus. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6 and IL-1beta as cytokines induced in an AhR-dependent manner in S. aureus-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6 and IL-1beta upon stimulation with living S. aureus. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen S. aureus in keratinocytes.

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The association of functional polymorphisms in the aryl hydrocarbon receptor ( AHR ) gene with the risk of vitiligo in Han Chinese populations

British Journal of Dermatology ◽

10.1111/j.1365-2133.2011.10798.x ◽

2012 ◽

Vol 166 (5) ◽

pp. 1081-1087 ◽

Cited By ~ 21

Author(s):

X‐W. Wang ◽

K. Li ◽

S. Guo ◽

H‐N. Qiang ◽

L. Liu ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Han Chinese ◽

Chinese Populations ◽

Functional Polymorphisms ◽

Aryl Hydrocarbon ◽

Ahr Gene

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Assessment of the Aryl Hydrocarbon Receptor Gene as a Therapeutic Target in Childhood T-Lineage Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v106.11.536.536 ◽

2005 ◽

Vol 106 (11) ◽

pp. 536-536

Author(s):

Marrit Meier ◽

Monique L. den Boer ◽

Mathilde J.C. Broekhuis ◽

Ronald W. Stam ◽

Elisabeth R. van Wering ◽

...

Keyword(s):

Synergistic Effect ◽

Aryl Hydrocarbon Receptor ◽

Therapeutic Target ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Mrna Levels ◽

Childhood All ◽

Aryl Hydrocarbon ◽

Fold Induction ◽

Ahr Gene

Abstract T-lineage ALL is an unfavorable subtype of childhood ALL and is associated with in-vitro resistance to drugs. Therefore the identification of novel genes that may serve as targets to modulate drug resistance is desirable. We compared the gene expression profile of 28 pediatric T-ALL patients being either sensitive (DNRS) or resistant (DNRR) to daunorubicin. The aryl hydrocarbon receptor (AHR) gene appeared to be highly discriminating between DNRS and DNRR T-ALL patients. AHR is known to mediate signal transduction in response to xenobiotics by activating the transcription of xenobiotic-responsive genes such as CYP1A1 and CYP1A2. Expression analysis by real-time quantitative PCR confirmed that basal AHR mRNA levels in ALL cells derived from patients is correlated with DNR resistance (Rs=0.41, P=0.02). Exposure to DNR of the REH cell line expressing a low AHR level led to a 40-fold induction of AHR mRNA. In two other cell lines (i.e. HL60 and SEMK-2) expressing high levels of AHR the upregulation was only 1.4-fold. In REH, the 40-fold induction of AHR after DNR exposure was inhibited by 40% after pre-exposure to the AHR inhibitors salicylamide (SAL) and geldanamycin (GA). Pre-incubation of leukemic cells of T-ALL patients with SAL or GA prior to DNR exposure had a synergistic effect on DNR sensitivity. In addition, transfection of SEMK-2 cells with AHR-specific siRNA resulted in the reduction of AHR expression by 80% after 24 h and had also a synergistic effect on DNR induced cell kill up to 96 hours after siRNA treatment. We conclude that a high expression of the AHR gene is involved in DNR resistance in childhood T-ALL and that AHR may serve as a very attractive new therapeutic target.

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Lack of association between multiple polymorphisms in aryl hydrocarbon receptor (AhR) gene and cancer susceptibility

Environmental Health and Preventive Medicine ◽

10.1186/s12199-020-00907-z ◽

2020 ◽

Vol 25 (1) ◽

Author(s):

He Li ◽

Li Luo ◽

Dan Wang ◽

Jun Duan ◽

Rui Zhang

Keyword(s):

Sensitivity Analysis ◽

Cancer Risk ◽

Aryl Hydrocarbon Receptor ◽

Cancer Susceptibility ◽

Meta Analysis ◽

Cancer Type ◽

China National Knowledge Infrastructure ◽

Aryl Hydrocarbon ◽

Negative Results ◽

Ahr Gene

Abstract Background The aryl hydrocarbon receptor (AhR) is commonly known as an environmental sensor. Polymorphisms in AhR gene have been implicated in susceptibility to cancer. However, the results were controversial. This study was conducted to quantitatively summarize the association between AhR polymorphisms and cancer risk by meta-analysis. Methods Relevant reports were searched in four databases (Embase, PubMed, Wanfang, and China National Knowledge Infrastructure). We used pooled odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the strength of the association in both standard and cumulative meta-analysis. Subgroup and sensitivity analysis was also performed, and between-study heterogeneity and publication bias were checked. Results A total of seventeen studies referring to three AhR polymorphisms (rs2066853, rs7796976, and rs2074113) were identified, and 9557 cases and 10038 controls were included. There was no statistically significant association of AhR rs2066853 polymorphism with cancer risk in the overall population, and the negative results were repeated in subgroup analysis by the ethnicity and cancer type. Concerning AhR rs7796976 or rs2074113 polymorphism, no significant correlation was detected. Moreover, these non-significant findings were stable in sensitivity analysis, and the cumulative meta-analysis indicated a trend of no significant link between this three AhR polymorphisms and cancer risk as more data accumulated over time. Conclusion This meta-analysis provides evidence that the rs2066853, rs7796976, or rs2074113 polymorphism in AhR gene is not a susceptible predictor of cancer. Further clinical and functional investigation between AhR polymorphisms and cancer susceptibility are needed.

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Role of NF-kB RelB in Aryl Hydrocarbon Receptor-Mediated Ligand Specific Effects

International Journal of Molecular Sciences ◽

10.3390/ijms20112652 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2652 ◽

Cited By ~ 2

Author(s):

Yasuhiro Ishihara ◽

Sarah Y. Kado ◽

Christiane Hoeper ◽

Shelly Harel ◽

Christoph F. A. Vogel

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Functional Expression ◽

Dependent Manner ◽

Induced Expression ◽

Aryl Hydrocarbon ◽

Regulatory Enzymes ◽

Basal Expression ◽

Expression Of Genes ◽

Ahr Gene

Here, we investigate the role of RelB in the regulation of genes which were identified to be induced in an aryl hydrocarbon receptor (AhR)-dependent manner and critically involved in regulation of immune responses. We analyzed the expression of genes of the AhR gene battery, cytokines, and immune regulatory enzymes in bone marrow-derived macrophages (BMM) and thymus of B6 wildtype (wt) mice and RelB knockout (RelB−/−) mice after treatment with various AhR ligands. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced expression of indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 was significantly repressed in thymus of RelB−/− mice but not in BMM derived from RelB−/− mice. Interestingly, the induced and basal expression of the cytokines interleukin (IL)-17A, IL-22, and CCL20 required the functional expression of RelB. The RelB-dependent expression of CCL20 was induced by the AhR ligands TCDD and 6-formylindolo[3,2-b]carbazole (FICZ), whereas indole-3-carbinol (I3C) suppressed CCL20 in lipopolysaccharide (LPS)-activated wt BMM. The LPS-induced expression of IL-6 and IL-10 was enhanced by TCDD and FICZ, whereas I3C significantly suppressed these cytokines in BMM. The exposure to FICZ led to higher increases of IL-17A and IL-22 mRNA compared to the effect of TCDD or I3C in thymus of wt mice. On the other hand, TCDD was the strongest inducer of CYP1A1, AhR Repressor (AhRR), and IDO2. In summary, these findings provide evidence for the important role of RelB in the transcriptional regulation of cytokines and enzymes induced by AhR ligands.

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A case of cyclical Cushing's disease associated with corticosteroidbinding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease

Acta Endocrinologica ◽

10.1530/eje.0.1330317 ◽

1995 ◽

Vol 133 (3) ◽

pp. 317-319 ◽

Cited By ~ 9

Author(s):

Hajime Watanobe ◽

Takeshi Nigawara ◽

Ryo Nasushita ◽

Shinsuke Sasaki ◽

Kazuo Takebe

Keyword(s):

Cushing’S Disease ◽

Cushing's Disease ◽

Plasma Acth ◽

School Of Medicine ◽

Corticosteroid Binding Globulin ◽

High Urinary Excretion ◽

Cortisol Levels ◽

Cyclical Cushing’S Disease ◽

Free Plasma ◽

Periodic Secretion

Watanobe H, Nigawara T, Nasushita R, Sasaki S, Takebe K. A case of cyclical Cushing's disease associated with corticosteroid-binding globulin deficiency: a rare pitfall in the diagnosis of Cushing's disease. Eur J Endocrinol 1995;133:317–9. ISSN 0804–4643 We experienced an extremely unusual combination of Cushing's disease and corticosteroid-binding globulin (CBG) deficiency that has been reported in only one similar case to date. A 53-year-old woman presented at a medical clinic with clinical Cushing's disease. However, her plasma levels of adrenocorticotropin (ACTH) and cortisol were in the normal range. Six months later, during a second visit, a high urinary excretion of 17-hydroxycorticosteroids was found, but plasma ACTH and cortisol levels were normal again. Further investigation revealed a decreased CBG concentration. Free plasma cortisol levels were clearly elevated. Furthermore, the Cushing's disease of our patient was complicated by periodic secretion of ACTH and cortisol, with high or normal outputs of corticosteroids occurring alternately every 1–3 days, which explained the occasionally normal plasma ACTH and cortisol levels. A combination of a decreased serum CBG concentration and periodic secretion of ACTH can be an important pitfall in the diagnosis of Cushing's disease. Hajime Watanobe, Third Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036, Japan

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