Dataset Information

Cathelicidins and the Onset of Labour.

ABSTRACT: Preterm birth, defined as delivery before 37 weeks of gestation, is the leading cause of neonatal mortality and morbidity. Infection and inflammation are frequent antecedents of spontaneous preterm birth. Cathelicidin, an antimicrobial host defence peptide, is induced by infection and inflammation and although expressed in the reproductive tract and fetal tissues, its role in the pathogenesis of spontaneous preterm birth is unknown. Here we demonstrate that cathelicidin expression is increased at RNA and protein level in the mouse uterus in a model of inflammation-induced labour, where ultrasound guided intrauterine injection of lipopolysaccharide (LPS) at E17 stimulates preterm delivery within 24?hours. Cathelicidin-deficient (Camp^-/-) mice are less susceptible to preterm delivery than wild type mice following intrauterine injection of 1??g of LPS, and this is accompanied by a decrease in circulating IL-6, an inflammatory mediator implicated in the onset of labour. We also show that the proportion of cathelicidin expressing cells in the myometrium is higher in samples obtained from women in labour at term than pre-labour. Together, these data suggest that cathelicidin has roles in mediating pro-inflammatory responses in a murine model of inflammation-induced labour, and in human term labour.

SUBMITTER: Boeckel SRV

PROVIDER: S-EPMC6517412 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Cathelicidins and the Onset of Labour.

Boeckel Sara R van SRV Hrabalkova Lenka L Baker Tina L TL MacPherson Heather H Frew Lorraine L Boyle Ashley K AK McHugh Brian J BJ Wilson Kirsten K Norman Jane E JE Dorin Julia R JR Davidson Donald J DJ Stock Sarah J SJ

Scientific reports 20190514 1

Preterm birth, defined as delivery before 37 weeks of gestation, is the leading cause of neonatal mortality and morbidity. Infection and inflammation are frequent antecedents of spontaneous preterm birth. Cathelicidin, an antimicrobial host defence peptide, is induced by infection and inflammation and although expressed in the reproductive tract and fetal tissues, its role in the pathogenesis of spontaneous preterm birth is unknown. Here we demonstrate that cathelicidin expression is increased a ...[more]

PMID: 31089176

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Project description:In this study, dodecapeptide cathelicidins were shown to be widespread antimicrobial peptides among the Cetruminantia clade. In particular, we investigated the dodecapeptide from the domestic goat Capra hircus, designated as ChDode and its unique ortholog from the sperm whale Physeter catodon (PcDode). ChDode contains two cysteine residues, while PcDode consists of two dodecapeptide building blocks and contains four cysteine residues. The recombinant analogs of the peptides were obtained by heterologous expression in Escherichia coli cells. The structures of the peptides were studied by circular dichroism (CD), FTIR, and NMR spectroscopy. It was demonstrated that PcDode adopts a β-hairpin structure in water and resembles β-hairpin antimicrobial peptides, while ChDode forms a β-structural antiparallel covalent dimer, stabilized by two intermonomer disulfide bonds. Both peptides reveal a significant right-handed twist about 200 degrees per 8 residues. In DPC micelles ChDode forms flat β-structural tetramers by antiparallel non-covalent association of the dimers. The tetramers incorporate into the micelles in transmembrane orientation. Incorporation into the micelles and dimerization significantly diminished the amplitude of backbone motions of ChDode at the picosecond-nanosecond timescale. When interacting with negatively charged membranes containing phosphatidylethanolamine (PE) and phosphatidylglycerol (PG), the ChDode peptide adopted similar oligomeric structure and was capable to form ion-conducting pores without membrane lysis. Despite modest antibacterial activity of ChDode, a considerable synergistic effect of this peptide in combination with another goat cathelicidin - the α-helical peptide ChMAP-28 was observed. This effect is based on an increase in permeability of bacterial membranes. In turn, this mechanism can lead to an increase in the efficiency of the combined action of the synergistic pair ChMAP-28 with the Pro-rich peptide mini-ChBac7.5Nα targeting the bacterial ribosome.

Project description:Changes in cell phenotype are thought to occur through the expression of groups of co-regulated genes within topologically associated domains (TADs). In this paper, we allocate genes expressed within the myometrium of the human uterus during the onset of term labour into TADs. Transformation of the myometrial cells of the uterus into a contractile phenotype during term human labour is the result of a complex interaction of different epigenomic and genomic layers. Recent work suggests that the transcription factor (TF) RELA lies at the top of this regulatory network. Using deep RNA sequencing (RNAseq) analysis of myometrial samples (n = 16) obtained at term from women undergoing caesarean section prior to or after the onset of labour, we have identified evidence for how other gene expression regulatory elements interact with TFs in the labour phenotype transition. Gene set enrichment analysis of our RNAseq data identified three modules of enriched genes (M1, M2 and M3), which in gene ontology studies are linked to matrix degradation, smooth muscle and immune gene signatures, respectively. These genes were predominantly located within chromosomal TADs suggesting co-regulation of expression. Our transcriptomic analysis also identified significant differences in the expression of long non-coding RNAs (lncRNA), microRNAs (miRNA) and TFs that were predicted to target genes within the TADs. Additionally, network analysis revealed 15 new lncRNA (MCM3AP-AS1, TUG1, MIR29B2CHG, HCG18, LINC00963, KCNQ1OT1, NEAT1, HELLPAR, SNHG16, NUTM2B-AS1, MALAT1, PSMA3-AS1, GABPB1-AS1, NORAD and NKILA) and 4 miRNA (mir-145, mir-223, mir-let-7a and mir-132) as top gene hubs with three TFs (NFKB1, RELA and ESR1) as master regulators. Together, these factors are likely to be involved in co-regulatory networks driving a myometrial transformation to generate an estrogen-sensitive phenotype. We conclude that lncRNA and miRNA targeting the estrogen receptor 1 and nuclear factor kappa B pathways play a key role in the initiation of human labour. For the first time, we perform an integrative analysis to present a multi-level genomic signature made of mRNA, non-coding RNA and TFs in the myometrium for spontaneous term labour.

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Cathelicidins and the Onset of Labour.

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Cathelicidins and the Onset of Labour.

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