visualization-estrogen-receptors-colons-mice-with-tnbs-induced-crohn

Visualization of Estrogen Receptors in Colons of Mice with TNBS-Induced Crohn's Disease using Immunofluorescence

Crohn&#39;s disease is the most diagnosed type of inflammatory bowel disease. Chronic inflammation developing in the intestine leads to peristalsis ...

University of Lodz

Estrogens play a crucial role in the regulation of physiological and pathophysiological processes. These hormones act through specific receptors, most notably the canonical estrogen receptors α and β (ERα and ERβ) and their truncated forms as well as the G protein-coupled estrogen receptor (GPER). Several studies have shown that GPER is expressed in many normal and cancer cells, including those of the breast, endometrium, ovary, testis and lung. Hormonal imbalance is one possible cause of cancer development. An accumulating body of evidence indicates that GPER is involved in the regulation of cancer cell proliferation, migration and invasion, it may act as a mediator of microRNA, and is believed to modulate the inflammation associated with neoplastic transformation. Furthermore, used in various treatment regimens anti-estrogens such as tamoxifen, raloxifen and fulvestrant (ICI 182.780), antagonists/modulators of canonical estrogen receptors, were found to be GPER agonists. This review presents the current knowledge about the potential role of GPER in neoplastic transformation.

The G protein-coupled estrogen receptor as a modulator of neoplastic transformation.

To investigate the levels of G protein-coupled receptor 55 (GPR55) expression in colonic tissue of inflammatory bowel disease (IBD) patients and healthy controls, and its potential implication in IBD treatment.

G protein-coupled receptor 55 (GPR55) expresses differently in patients with Crohn's disease and ulcerative colitis.

G protein-coupled receptor 30 (GPR30) is a recently de-orphanized estrogen receptor that mediates the effects of estrogens on different cells. It has been postulated that in inflammatory bowel diseases (IBD) activation of GPR30 blocks the pathways dependent on pro-inflammatory cytokines. The aim of our study was to investigate GPR30 expression in patients with IBD and its potential implication in future therapies.

G Protein-Coupled Receptor 30 (GPR30) Expression Pattern in Inflammatory Bowel Disease Patients Suggests its Key Role in the Inflammatory Process. A Preliminary Study.

The etiology and pathogenesis underlying irritable bowel syndrome (IBS), a common gastrointestinal disorder are still unclear. Cumulating data suggest dysregulation of inflammatory and immune response pathways and changes of epithelial barrier function. The role of estrogens albeit varied, in responses of immune system is well documented. The aim of this study was to investigate estrogen receptors engagment in IBS subtypes, i.e. constipation predominant (IBS-C) and diarrhea predominant (IBS-D). Furthermore, we analyzed whether estrogen signaling is accompanied by alteration in expression of pro- and anti-inflammatory cytokines and microRNAs that can regulate among others genes involved in immune responses. It was found that estrogen receptor α (ERα) and G protein-coupled estrogen receptor (GPER) expression is up-regulated in IBS while estrogen receptor β (ERβ) appears to be down-regulated at mRNA but up-regulated at the protein level. When gender and female age were included statistically significant overexpression of ERα in IBS-D women under the age of 50, while of GPER in IBS-D men was stated. In all studied IBS samples disturbances in expression of cytokines IL-6, IL-10 and TNF-α as well as miR-145, miR-148-5p and miR-592 were observed. This research reveals the association of estrogen receptors with IBS. Simultaneous alterations of studied immunomodulatory cytokines and microRNAs suggest that in IBS dysregulation of local immune response may involve estrogen-dependent way.

Estrogen signaling deregulation related with local immune response modulation in irritable bowel syndrome.

Estrogens exert immunomodulatory action in many autoimmune diseases. Accumulating evidence highlights the meaningful impact of estrogen receptors in physiology and pathophysiology of the colon. However, the significance of G protein-coupled estrogen receptor (GPER) on Crohn's disease (CD), one of the inflammatory bowel disease (IBD) types, is still elusive. Our study revealed GPER overexpression at the mRNA and protein levels in patients with CD. To evaluate the effects of GPER activation/inhibition on colitis development, a murine 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced model of CD was used. We showed that activation of GPER reduces mortality, improves macroscopic and microscopic scores and lowers C-reactive protein (CRP) level. The impact of estrogen signaling on the suppression of the intestinal inflammation was proved by immunohistochemistry. It was demonstrated that GPER activation is accompanied by modulation of extracellular-signal regulated kinase (ERK) signaling pathway and expression level of genes involved in signal transmission and immune response as well as the expression of some microRNAs (miR-145, miR-148-5p and miR-592). Our study revealed that the membrane-bound estrogen receptor GPER mediates anti-inflammatory action and seems to be a potent therapeutic target in maintaining remission in CD.

G protein-coupled estrogen receptor mediates anti-inflammatory action in Crohn's disease.

The pathogenesis of inflammatory bowel diseases (IBD) seems to be associated with alterations of immunoregulation. Several lines of evidence suggest that estrogens play a role in the modulation of immune responses and may be related to the etiology of IBD. The purpose of this work was to examine the involvement of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), estrogen receptor β (ERβ) and ERα spliced variants ERα36 and ERα46 in Crohn's disease (CD) and ulcerative colitis (UC). The studied group included 73 patients with IBD and 31 sex and age-related controls. No differences in serum levels of 17β-estradiol nor of CYP1A1 and SULT1E1 enzymes involved in estrogen catabolism were stated. The expression pattern of estrogen receptors in tissue samples was quantified using real-time PCR and Western blotting. Statistically significant up-regulation of GPER and ERα in both CD and UC as well as down-regulation of ERβ in CD patients was found. However, differences in the expression of estrogen receptors in CD and UC have been identified, depending on the sex and age of patients. In men, up-regulation of GPER, ERα and ERα46 expression was shown in CD and UC patients. In women under 50 years of age, GPER protein level increased in UC whereas ERβ expression tended to decrease in CD and UC patients. In turn, in women over 50 the protein level of ERα increased in UC while ERβ expression decreased in CD patients. Dysregulation of estrogen receptors in the intestinal mucosa of patients with CD and UC indicates that estrogen signaling may play a role in the local immune response and maintain epithelial homeostasis in a gender- and age-dependent manner.

Sex- and Age-Related Estrogen Signaling Alteration in Inflammatory Bowel Diseases: Modulatory Role of Estrogen Receptors.

Estrogens play important roles in the development and progression of multiple tumor types. Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast, endometrium and ovary, but also in the development of colorectal cancer (CRC). The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptors α and β, as well as the membrane-bound G protein-coupled estrogen receptor (GPER). The roles of GPER in CRC development and progression, however, remain poorly understood. Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases, such as Crohn's disease and ulcerative colitis. GPER is also involved in cell cycle regulation, endoplasmic reticulum stress, proliferation, apoptosis, vascularization, cell migration, and the regulation of fatty acid and estrogen metabolism in CRC cells. Thus, multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis. In this review, we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.

G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis.

Chemerin is a multifunctional protein involved among others in adipogenesis, angiogenesis and lipid as well as glucose metabolism. Chemerin is an essential factor in promotion of chemotaxis of numerous immune cell types and plays an important role in several pathophysiologic conditions. Chemerin receptors are present on monocytes/macrophages, T cells, natural killer and dendritic cells as well as neutrophils. However, the role of chemerin and chemerin receptors in immune response and gastrointestinal diseases is still poorly understood. Accumulating, clinical and experimental studies observed disturbation of chemerin and chemerin receptors in a number of disorders including Barrett's esophagus, esophageal cancer, gastric cancer, hepatic dysfunction, irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. Moreover, chemerin and chemerin receptors have been shown to regulate proliferation, migration and invasion of gastrointestinal and immune cells as well as cancer-associated fibroblasts. In this review we present the current state of knowledge about the contribution of chemerin to immune response and gastrointestinal disorders.

Article	Year
The G protein-coupled estrogen receptor as a modulator of neoplastic transformation. Molecular and cellular endocrinology\| PubMed ID: 27107933	2016
G protein-coupled receptor 55 (GPR55) expresses differently in patients with Crohn's disease and ulcerative colitis. Scandinavian journal of gastroenterology\| PubMed ID: 28272905	2017
G Protein-Coupled Receptor 30 (GPR30) Expression Pattern in Inflammatory Bowel Disease Patients Suggests its Key Role in the Inflammatory Process. A Preliminary Study. Journal of gastrointestinal and liver diseases : JGLD\| PubMed ID: 28338111	2017
Estrogen signaling deregulation related with local immune response modulation in irritable bowel syndrome. Molecular and cellular endocrinology\| PubMed ID: 28774781	2018
G protein-coupled estrogen receptor mediates anti-inflammatory action in Crohn's disease. Scientific reports\| PubMed ID: 31043642	2019
Sex- and Age-Related Estrogen Signaling Alteration in Inflammatory Bowel Diseases: Modulatory Role of Estrogen Receptors. International journal of molecular sciences\| PubMed ID: 31261736	2019
G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis. World journal of gastroenterology\| PubMed ID: 31435166	2019
Chemerin in immune response and gastrointestinal pathophysiology. Clinica chimica acta; international journal of clinical chemistry\| PubMed ID: 32070869	2020

Damian Jacenik

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