Dataset Information

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

ABSTRACT: Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-?B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-?B 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-?B translocation into the nucleus that resulted in high NF-?B transcription activity. The overall magnitude of NF-?B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-?B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-?B 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-?B transcription factor.

SUBMITTER: Caballero I

PROVIDER: S-EPMC5256028 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Caballero Ignacio I Boyd James J Almiñana Carmen C Sánchez-López Javier A JA Basatvat Shaghayegh S Montazeri Mehrnaz M Maslehat Lay Nasim N Elliott Sarah S Spiller David G DG White Michael R H MR Fazeli Alireza A

Scientific reports 20170123

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 fo ...[more]

PMID: 28112187

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Project description:BackgroundToll-like receptors (TLRs) are sentinel receptors of the innate immune system. TLR4 detects bacterial lipopolysaccharide (LPS) and TLR5 detects bacterial flagellin. A common human nonsense polymorphism, TLR5:c.1174C>T, results in a non-functional TLR5 protein. Individuals carrying this variant have decreased mortality from melioidosis, infection caused by the flagellated Gram-negative bacterium Burkholderia pseudomallei. Although impaired flagellin-dependent signaling in carriers of TLR5:c.1174C>T is well established, this study tested the hypothesis that a functional effect of TLR5:c.1174C>T is flagellin-independent and involves LPS-TLR4 pathways.Methodology/principal findingsWhole blood from two independent cohorts of individuals genotyped at TLR5:c.1174C>T was stimulated with wild type or aflagellated B. pseudomallei or purified bacterial motifs followed by plasma cytokine measurements. Blood from individuals carrying the TLR5:c.1174C>T variant produced less IL-6 and IL-10 in response to an aflagellated B. pseudomallei mutant and less IL-8 in response to purified B. pseudomallei LPS than blood from individuals without the variant. TLR5 expression in THP1 cells was silenced using siRNA; these cells were stimulated with LPS before cytokine levels in cell supernatants were quantified by ELISA. In these cells following LPS stimulation, silencing of TLR5 with siRNA reduced both TNF-α and IL-8 levels. These effects were not explained by differences in TLR4 mRNA expression or NF-κB or IRF activation.Conclusions/significanceThe effects of the common nonsense TLR5:c.1174C>T polymorphism on the host inflammatory response to B. pseudomallei may not be restricted to flagellin-driven pathways. Moreover, TLR5 may modulate TLR4-dependent cytokine production. While these results may have broader implications for the role of TLR5 in the innate immune response in melioidosis and other conditions, further studies of the mechanisms underlying these observations are required.

Dataset Information

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

Publications

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

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