Dual Activation of Estrogen Receptor Alpha and Glucocorticoid Receptor Upregulate CRTh2-Mediated Type 2 Inflammation; Mechanism Driving Asthma Severity in Women?

Background: Type 2-high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant-homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC). Methods: Type 2 inflammation and the proportion of blood Th2 cells (CD4 CRTh2 ) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V , 7-AAD) were determined by flow cytometry, qRT-PCR, western blot and ELISA. Results: In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL-13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL-5 and IL-13 following CRTh2 activation than Th2 cells treated with GC alone. Conclusion: Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production. (249)

Download Full-text

IL-2 Modulates Th2 cell Responses to Glucocorticoid: A Cause of Persistent Type 2 Inflammation?

10.1101/365783 ◽

2018 ◽

Author(s):

Tharsan Kanagalingam ◽

Meerah Vijeyakumaran ◽

Nami Shrestha Palikhe ◽

Lauren Solomon ◽

Harissios Vliagoftis ◽

...

Keyword(s):

Peripheral Blood ◽

Blood Cells ◽

Asthma Severity ◽

Th2 Cells ◽

Peripheral Blood Cells ◽

Cell Responses ◽

Th2 Cell ◽

Type 2 Inflammation

ABSTRACTBackgroundInhaled glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine (IL-4, IL-5 and IL-13) expression and induce apoptosis. Asthma severity is associated with GC insensitivity, increased type 2 inflammation and circulating Th2 cells. Since IL-2 is a T cell survival factor, we assessed whether IL-2 levels associate with the proportion of Th2 cells and/or correlate with clinical features of asthma severity.MethodsPeripheral blood from asthma patients (n=18) was obtained and Th2 cell numbers determined by flow cytometry. Peripheral blood cells were activated with mitogen (24hrs) and supernatant levels of IL-2 and IL-13 measured by ELISA. In vitro differentiated Th2 cells were treated with dexamethasone and IL-2 and assessed for apoptosis by flow cytometry staining of Annexin V. Level of mRNA for anti-apoptotic (BCL-2) and pro-apoptotic (BIM) genes as well as IL-13 were determined by qRT-PCR.ResultsIL-2 produced by activated peripheral blood cells correlated negatively with lung function (FEV1) and positively with daily dose of inhaled GC. When patients were stratified based on IL-2 level, high IL-2 producers made more IL-13 and had more circulating Th2 cells. In vitro, increasing the level of IL-2 in the culture media was associated with resistance to DEX-induced apoptosis, more BCL-2 and less BIM mRNA. Th2 cells cultured with higher IL-2 also had more IL-13 mRNA and required higher concentrations of DEX for cytokine suppression.Conclusions and Clinical RelevanceIL-2 modulates Th2 cell responses to GC, supporting both their survival and pro-inflammatory capacity, suggesting that a patient’s potential to produce IL-2 may be a determinant in asthma severity.

Download Full-text

ILC2 Cells Promote Th2 Cell Differentiation in AECOPD Through Activated Notch-GATA3 Signaling Pathway

Frontiers in Immunology ◽

10.3389/fimmu.2021.685400 ◽

2021 ◽

Vol 12 ◽

Author(s):

Min Jiang ◽

Ren Cai ◽

Jing Wang ◽

Zheng Li ◽

Dan Xu ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Peripheral Blood ◽

Culture Supernatant ◽

Th2 Cells ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Protein Levels ◽

Th2 Cell

This study is to investigate the capacity of type 2 innate lymphoid cells (ILC2s) in regulating the Th2 type adaptive immune response of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The study enrolled healthy people, stable chronic obstructive pulmonary disease (COPD) patients, and AECOPD patients. Flow cytometry was used to detect Th2 and ILC2 cells in the peripheral blood. In addition, ILC2s from the peripheral blood of AECOPD patients were stimulated with PBS, IL-33, Jagged1, DAPT, IL-33+Jagged1, IL-33+DAPT, and IL-33+Jagged-1+DAP in vitro. The levels of cytokines in the culture supernatant were detected by ELISA and the culture supernatant was used to culture CD4 + T cells. The mRNA and protein levels of Notch1, hes1, GATA3, RORα, and NF-κB of ILC2s were detected by real-time PCR and Western blot. The proportion of Th2 and ILC2s was significantly increased in the peripheral blood of AECOPD patients, alone with the increased Notch1, hes1, and GATA3 mRNA levels. In vitro results showed that the mRNA and protein levels of Notch1, hes1, GATA3 and NF-κB were significantly increased after stimulation with Notch agonist, meanwhile, the level of type 2 cytokines were increased in the supernatant of cells stimulated with Notch agonist, and significantly promoted differentiation of Th2 cells in vitro. Disruption of Notch pathway weakened GATA3 expression and cytokine production, and ultimately affected the differentiation of Th2 cells. In conclusion, our results suggest that ILC2s can promote Th2 cell differentiation in AECOPD via activated Notch-GATA3 signal pathway.

Download Full-text

Development of a Graphical User Interface Application to Identify Marginal and Potent Ligands for Estrogen Receptor Alpha

Indonesian Journal of Chemistry ◽

10.22146/ijc.34561 ◽

2019 ◽

Vol 19 (2) ◽

pp. 531 ◽

Cited By ~ 1

Author(s):

Nunung Yuniarti ◽

Sudi Mungkasi ◽

Sri Hartati Yuliani ◽

Enade Perdana Istyastono

Keyword(s):

Estrogen Receptor ◽

User Interface ◽

Graphical User Interface ◽

Estrogen Receptor Alpha ◽

Predictive Ability ◽

In Vitro Test ◽

Ligand Interaction ◽

Qsar Analysis ◽

Receptor Alpha

Employing ensemble Protein-Ligand Interaction Fingerprints (ensPLIF) as descriptors in post retrospective Structure-Based Virtual Screening (SBVS) campaigns Quantitative Structure-Activity Relationship (QSAR) analysis has been proven to significantly increase the predictive ability in the identification of potent ligands for estrogen receptor alpha (ERα). In the research presented in this article, similar approaches have been performed to construct and retrospectively validate an SBVS protocol to identify marginal ligands for ERα. Based on both validated SBVS protocols, a graphical-user-interface (GUI) application to identify if a compound is a non-, moderate or potent ligand for ERα was developed. The GUI application was subsequently used to virtually screen genistin, genistein, daidzin, and daidzein, followed by in vitro test employing a cytotoxic assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method.

Download Full-text

Estrogen receptor alpha gene variants associate with type 2 diabetes and fasting plasma glucose

Pharmacogenetics and Genomics ◽

10.1097/fpc.0b013e32831101ef ◽

2008 ◽

Vol 18 (11) ◽

pp. 967-975 ◽

Cited By ~ 22

Author(s):

Ingrid Dahlman ◽

Martine Vaxillaire ◽

Maria Nilsson ◽

Cecile Lecoeur ◽

Harvest F. Gu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Estrogen Receptor ◽

Plasma Glucose ◽

Fasting Plasma Glucose ◽

Estrogen Receptor Alpha ◽

Gene Variants ◽

Receptor Alpha ◽

Estrogen Receptor Alpha Gene ◽

Alpha Gene

Download Full-text

MP68-13 ESTROGEN RECEPTOR ALPHA PREVENTS BLADDER CANCER VIA INPP4B INHIBITED AKT PATHWAY IN VITRO AND IN VIVO

The Journal of Urology ◽

10.1016/j.juro.2015.02.2475 ◽

2015 ◽

Vol 193 (4S) ◽

Author(s):

Chiuan-Ren Yeh ◽

Iawen Hsu ◽

Hiroshi Miyamoto ◽

Xue-Ru Wu ◽

Chawnshang Chang ◽

...

Keyword(s):

Bladder Cancer ◽

Estrogen Receptor ◽

Estrogen Receptor Alpha ◽

Akt Pathway ◽

Receptor Alpha

Download Full-text

54 PREVENTION OF OBESITY, INSULIN RESISTANCE AND TYPE 2 DIABETES BY ESTROGENS: CRUCIAL ROLE OF ESTROGEN RECEPTOR ALPHA

Maturitas ◽

10.1016/s0378-5122(12)70058-0 ◽

2012 ◽

Vol 71 ◽

pp. S12

Author(s):

S. O'Brien

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Estrogen Receptor ◽

Crucial Role ◽

Estrogen Receptor Alpha ◽

Receptor Alpha

Download Full-text

Computer-Aided Drug Repurposing: A Cyclooxygenase-2 Inhibitor Celecoxib as a Ligand for Estrogen Receptor Alpha

Indonesian Journal of Chemistry ◽

10.22146/ijc.21196 ◽

2015 ◽

Vol 15 (3) ◽

pp. 274-280 ◽

Cited By ~ 3

Author(s):

Enade Perdana Istyastono ◽

Florentinus Dika Octa Riswanto ◽

Sri Hartati Yuliani

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

In Silico ◽

Estrogen Receptor Alpha ◽

Cyclooxygenase 2 ◽

Cytotoxic Activities ◽

In Vitro Test ◽

Receptor Alpha ◽

Vitro Test

A cyclooxygenase-2 (COX-2) inhibitor celecoxib has been previously reported to have cytotoxic activities towards gastric, prostate, ovarian, colon and breast cancer cell lines. This article reports that the cytotoxic activities of celecoxib could be resulted from its activity as a potent ligand for estrogen receptor alpha (ERα). Aided by molecular docking simulations, an in silico test to examine whether celecoxib is a ligand for estrogen receptor alpha (ERα) was performed followed by in vitro test employing cytotoxic assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method. The compound was extracted from Celebrex®. Measured by using UV spectrophotometric method at 255.5 nm, it was identified that the content of celecoxib was 102.15 mg/271.48 mg capsule content. The in silico test indicated that celecoxib is a potent ligand for ERα. This finding was confirmed experimentally by an in vitro test that celecoxib has a comparable activity as an ERα ligand to tamoxifen, a drug of choice for breast cancer treatment.

Download Full-text

Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications

Physiological Reviews ◽

10.1152/physrev.00024.2016 ◽

2017 ◽

Vol 97 (3) ◽

pp. 1045-1087 ◽

Cited By ~ 122

Author(s):

Jean-Francois Arnal ◽

Françoise Lenfant ◽

Raphaël Metivier ◽

Gilles Flouriot ◽

Daniel Henrion ◽

...

Keyword(s):

Estrogen Receptor ◽

Estrogen Receptor Alpha ◽

Reproductive Tract ◽

Vascular System ◽

Physiological Role ◽

Receptor Alpha ◽

Nuclear Signaling ◽

Nuclear Estrogen Receptor

Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.

Download Full-text