Abstract:Problem
Estradiol can directly affect epithelial cells or indirectly affect epithelial cells via stromal fibroblast secretion of growth factors, such as keratinocyte growth factor (KGF). The purpose of the present study was to determine if estradiol regulates constitutive as well as KGF-induced uterine epithelial cell secretion of CCL20 and CXCL1.
Method of Study
Freshly isolated and polarized uterine epithelial cells from Balb/c mice were cultured with estradiol in the presence or absence of KGF. CCL20 and … Show more
“…This lymphocyte chemokine is active in the mucosal adaptive immune response in the gastrointestinal tract, particularly in response to bacterial infection [ 46 , 47 ] [ 48 , 49 ]. While we could not find any description of CCL20 induction by GC specifically, there is evidence that production of this chemokine can be induced by bacterial products [ 50 ] and is suppressed by estrogen [ 51 ], which together would explain its particularly potent induction in diestrus infection. Fig.…”
BackgroundThe emergence of fully antimicrobial resistant Neisseria gonorrhoeae has led global public health agencies to identify a critical need for next generation anti-gonococcal pharmaceuticals. The development and success of these compounds will rely upon valid pre-clinical models of gonorrhoeae infection. We recently developed and reported the first model of upper genital tract gonococcal infection. During initial characterization, we observed significant reproductive cycle-based variation in infection outcome. When uterine infection occurred in the diestrus phase, there was significantly greater pathology than during estrus phase. The aim of this study was to evaluate transcriptional profiles of infected uterine tissue from mice in either estrus or diestrus phase in order to elucidate possible mechanisms for these differences.ResultsGenes and biological pathways with phase-independent induction during infection showed a chemokine dominant cytokine response to Neisseria gonorrhoeae. Despite general induction being phase-independent, this common anti-gonococcal response demonstrated greater induction during diestrus phase infection. Greater activity of granulocyte adhesion and diapedesis regulators during diestrus infection, particularly in chemokines and diapedesis regulators, was also shown. In addition to a greater induction of the common anti-gonococcal response, Gene Set Enrichment Analysis identified a diestrus-specific induction of type-1 interferon signaling pathways.ConclusionsThis transcriptional analysis of murine uterine gonococcal infection during distinct points in the natural reproductive cycle provided evidence for a common anti-gonococcal response characterized by significant induction of granulocyte chemokine expression and high proinflammatory mediators. The basic biology of this host response to N. gonorrhoeae in estrus and diestrus is similar at the pathway level but varies drastically in magnitude. Overlaying this, we observed type-1 interferon induction specifically in diestrus infection where greater pathology is observed. This supports recent work suggesting this pathway has a significant, possibly host-detrimental, function in gonococcal infection. Together these findings lay the groundwork for further examination of the role of interferons in gonococcal infection. Additionally, this work enables the implementation of the diestrus uterine infection model using the newly characterized host response as a marker of pathology and its prevention as a correlate of candidate vaccine efficacy and ability to protect against the devastating consequences of N. gonorrhoeae-associated sequelae.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5000-7) contains supplementary material, which is available to authorized users.
“…This lymphocyte chemokine is active in the mucosal adaptive immune response in the gastrointestinal tract, particularly in response to bacterial infection [ 46 , 47 ] [ 48 , 49 ]. While we could not find any description of CCL20 induction by GC specifically, there is evidence that production of this chemokine can be induced by bacterial products [ 50 ] and is suppressed by estrogen [ 51 ], which together would explain its particularly potent induction in diestrus infection. Fig.…”
BackgroundThe emergence of fully antimicrobial resistant Neisseria gonorrhoeae has led global public health agencies to identify a critical need for next generation anti-gonococcal pharmaceuticals. The development and success of these compounds will rely upon valid pre-clinical models of gonorrhoeae infection. We recently developed and reported the first model of upper genital tract gonococcal infection. During initial characterization, we observed significant reproductive cycle-based variation in infection outcome. When uterine infection occurred in the diestrus phase, there was significantly greater pathology than during estrus phase. The aim of this study was to evaluate transcriptional profiles of infected uterine tissue from mice in either estrus or diestrus phase in order to elucidate possible mechanisms for these differences.ResultsGenes and biological pathways with phase-independent induction during infection showed a chemokine dominant cytokine response to Neisseria gonorrhoeae. Despite general induction being phase-independent, this common anti-gonococcal response demonstrated greater induction during diestrus phase infection. Greater activity of granulocyte adhesion and diapedesis regulators during diestrus infection, particularly in chemokines and diapedesis regulators, was also shown. In addition to a greater induction of the common anti-gonococcal response, Gene Set Enrichment Analysis identified a diestrus-specific induction of type-1 interferon signaling pathways.ConclusionsThis transcriptional analysis of murine uterine gonococcal infection during distinct points in the natural reproductive cycle provided evidence for a common anti-gonococcal response characterized by significant induction of granulocyte chemokine expression and high proinflammatory mediators. The basic biology of this host response to N. gonorrhoeae in estrus and diestrus is similar at the pathway level but varies drastically in magnitude. Overlaying this, we observed type-1 interferon induction specifically in diestrus infection where greater pathology is observed. This supports recent work suggesting this pathway has a significant, possibly host-detrimental, function in gonococcal infection. Together these findings lay the groundwork for further examination of the role of interferons in gonococcal infection. Additionally, this work enables the implementation of the diestrus uterine infection model using the newly characterized host response as a marker of pathology and its prevention as a correlate of candidate vaccine efficacy and ability to protect against the devastating consequences of N. gonorrhoeae-associated sequelae.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-5000-7) contains supplementary material, which is available to authorized users.
“…CXCL1, a major neutrophil chemoattractant expressed by astrocytes and microglia, affects chemoattraction through its receptor CXCR2, which is present on diverse cellular populations, including leukocytes, keratinocytes, dermal fibroblasts, neutrophils, and OLs ( 40 , 41 ). E2 has been shown to be a negative regulator of CXCL1/CXCR2 signaling pathways ( 42 – 45 ) through predominantly ERα-dependent pathways ( 42 ). However, CXCL1-mediated functions extend beyond chemoattraction.…”
SignificanceCXCL1 is a major neutrophil chemoattractant that binds to the chemokine receptor, CXCR2, on neutrophils and oligodendrocytes. Estrogen receptor β ligand treatment in a mouse model of multiple sclerosis induces an increase in peripheral and brain CXCL1 levels that correlate with an increase in axon remyelination. Oligodendrocyte progenitor recruitment and differentiation by CXCL1, in combination with attenuated IFN-γ production reducing apoptosis, may account for at least one avenue whereby estrogen receptor β ligands exert their clinical benefits.
“…A study has found that both estrogen and tamoxifen significantly down-regulate the expression of CCR2 by murine monocytes and that they downregulate the expression of CXCR3 by murine monocytes to a lesser extent at the same time (88). Estradiol inhibited CCL20 secretion at 48 hr in freshly isolated and polarized uterine epithelial cells of BALB/c mice, regardless of whether keratinocyte growth factor (KGF) was present or not (89). Raloxifene is a selective estrogen receptor modulator (SERMs) and a promising treatment for experimental autoimmune encephalomyelitis (EAE).…”
Section: Chemokinesmentioning
confidence: 99%
“…Estrogen is thought to be a key regulator of CCL20 and CXCL1 in the upper female reproductive tract since it decreases the secretion of CCL20 but it directly increases the levels of CXCL1 in uterine epithelial cells (92). Estrogen enhances KGF-induced CXCL1 secretion in freshly isolated and polarized uterine epithelial cells at 24 hr (89). In Foxp3-deficient mice with EAE, estrogen (17b-estradiol, E2) suppressed the expression and proliferation of CCL2 and CXCL2 but it enhanced the secretion of interleukin-10 (IL-10) and IL-13 by myelin oligodendrocyte glycoprotein (MOG)-35-55-specific spleen cells.…”
Section: Chemokinesmentioning
confidence: 99%
“…CXCL8 (interleukin-8), a member of the CXC family, is overexpressed in ERα-negative breast cancer cell lines while a high level of CXCL8 expression in tumors is closely correlated with the activating protein-1 (AP-1) pathway and somewhat correlated with the NF-кB pathway (98). The inhibitory effect of estradiol or raloxifene on CCL20 secretion and function was reversed by administration of an estrogen receptor antagonist designated ICI 182,780 (89,90). ERα antagonists mediate CCL20 and CXCL1 secretion while ERβ does not.…”
Section: The Mechanism By Which Estrogen Modulates Chemokinesmentioning
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