Hormone Modulation of Toll-Like Receptor 5 in Cultured Human Bladder Epithelial Cells

Foust-Wright, Caroline; Pulliam, Samantha J.; Batalden, Rebecca Posthuma; Berk, Tucker; Weinstein, Milena M.; Wakamatsu, May; Phillippe, Mark

doi:10.1177/1933719116667489

Cited by 11 publications

(6 citation statements)

References 22 publications

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“…Cross-talk between ERs and other transcription factors seems to play an important role in the regulation of TLR5 mediated gene expression25. Incubation of human bladder epithelial cells with estradiol (E2) downregulates TLR5 expression but increases TLR5-dependent IL-6 secretion26. However, no response to flagellin is observed in E2 producing granulosa cells that express TLR52728.…”

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confidence: 99%

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

Caballero

Boyd

Almiñana

et al. 2017

Sci Rep

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Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-κB translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-κB signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-κB translocation into the nucleus that resulted in high NF-κB transcription activity. The overall magnitude of NF-κB transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-κB translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-κB transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-κB transcription factor.

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confidence: 99%

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

Caballero

Boyd

Almiñana

et al. 2017

Sci Rep

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“…TLR5 is a key host factor in detecting potential UPEC infections 17,28 . Reports using human bladder T24 cells suggest that estrogen treatment is linked to TLR5 suppression with prolonged flagellin exposure further reducing TLR5 protein concentrations as measured by ELISA 35 . In contrast, our VK2 E6/E7 microarray data analysed in response to estrogen and E + F treatments did not suggest changes in TLR5 expression.…”

Section: Discussionmentioning

confidence: 99%

Topical Estrogen Treatment Augments the Vaginal Response to Escherichia coli Flagellin

Stanton

Mowbray

Lanz

et al. 2020

Sci Rep

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The female climacteric or menopausal process characterised by reduced estrogen, associates with an increased risk of recurrent urinary tract infections (rUtis) linked to uropathogenic Escherichia coli (UPEC). Clinically, topical vaginal estrogen treatment has a prophylactic effect against such infections. The aim of this study was to investigate, in vitro, the effects of a topical estrogen treatment on vaginal epithelial responses following challenge with E.coli flagellin mimicking an UPEC challenge. Immortalised vaginal epithelial cells (VK2 E6/E7), modelling the vaginal epithelium were treated with either 4 nM 17β-estradiol (E) for seven days, 50 ng/ml E.coli flagellin (F) for 12 h, or 4 nM 17β-estradiol plus 50 ng/ml flagellin (E + F(12 h)). RNA was analysed by microarray gene profiling using the Illumina HumanHT-12 v 4 Expression Beadchip. Following E + F treatments expression of genes encoding host defence molecules including DEFβ4A, DEFB103A, LCN2 as well as those associated with keratinisation eg CNFN and SPRR family genes were significantly enhanced (P < 0.05) compared to either E or F treatments alone. Mutation of estrogen responsive elements (EREs) identified in the DEFβ4 gene promoter abolished the augmented gene expression suggesting estrogen functioned directly through a regulatory mechanism involving ESR1/2. Ingenuity pathway analyses also suggested the proinflammatory cytokine IL-17A to regulate the vaginal host defences during infection. Pre-treating VK2 E6/E7 cells with estrogen (4 nM) and challenging with 1L-17A & F (12 h) significantly enhanced DEFβ4, DEF103A and S100A7 expression (P < 0.05). Origins of vaginal IL-17 in vivo remain unclear, but patient biopsies support γδ T cells located within the vaginal epithelium. These data suggest that the vaginal antimicrobial response induced by flagellin activation of Toll-like Receptor 5 cell signalling is augmented following topical estrogen application.

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“…Notably, there is an inverse relationship between TLR5 expression and IL-6 production. Estradiol enhances IL-6 production, whereas progesterone intensifies it even further when compared to hormone-free or combined estrogen-progesterone environments [73]. Estradiol can also enhance TLR8 expression in human PBMCs.…”

Section: Mechanisms Of Action Of Androstane Neuroactive Steroids On T...mentioning

confidence: 95%

“…This leads to diminished phosphorylation of NF-κB and inhibits its expression and nuclear translocation. Progesterone also downregulates TLRs, MyD88 and CD14 levels and concomitant inflammatory cytokines while upregulating anti-inflammatory proteins such as suppressor of cytokine signaling (SOCS) 1 [69,[71][72][73]294,[307][308][309]. Furthermore, its structural similarities with pregnenolone Life 2024, 14,582 and allopregnanolone suggest it may share the same abilities to inhibit TLR activation described above.…”

Section: Mechanisms Of Action Of Pregnane Neuroactive Steroids On Tol...mentioning

confidence: 99%

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

Balan,

Boero,

Chéry

et al. 2024

Life

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Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.

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Hormone Modulation of Toll-Like Receptor 5 in Cultured Human Bladder Epithelial Cells

Cited by 11 publications

References 22 publications

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

Topical Estrogen Treatment Augments the Vaginal Response to Escherichia coli Flagellin

Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders

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