Polybacterial stimulation suggests discrete IL-6/IL-6R signaling in human fetal membranes: Potential implications on IL-6 bioactivity

Nathalia Mayumi Noda-Nicolau, Jossimara Polettini, Márcia Guimarães da Silva, Morgan R. Peltier, Ramkumar Menon

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The polybacterial invasion of the amniotic cavity and risk of preterm birth is often due to cervicovaginal bacteria such as genital mycoplasmas (Mycoplasma hominis and Ureaplasma urealyticum) and Gardnerella vaginalis. The most studied biomarker associated with preterm birth is interleukin-6 (IL-6), a pleiotropic cytokine that performs different functions based on classical or trans-signaling mechanisms. This study evaluated the changes in IL-6 and IL-6 function associated accessory molecules by human fetal membranes to determine the functional availability of IL-6 assessment in an in vitro model of polybacterial infection. Fetal membranes were treated with LPS or heat-inactivated genital mycoplasmas and G. vaginalis alone or in combination. IL-6 and its soluble receptors (sgp130, sIL-6R) were assessed in conditioned medium by immunoassays and membrane-bound receptors were evaluated in the tissue using immunohistochemistry and RT-PCR. Data from protein and gene expression were evaluated using linear mixed effects models. Data from immunohistochemistry were evaluated using one-way analysis of variance followed by the Tukey test. Genital mycoplasmas alone, or in combination, inhibited IL-6 trans-signaling with increased sgp130 production. G. vaginalis activated the classical IL-6 signaling pathway, as did LPS. Polybacterial treatment resulted in a balanced response with neither pathway being favored. The increase in IL-6 production by fetal membranes in response to infection is likely a non-specific innate response and not an indicator of a functional mediator of any labor-inducing pathways. This suggests that correlating the risk of adverse pregnancy outcomes and designing interventions based on IL-6 levels without considering soluble receptors may be an ineffective strategy.

Original languageEnglish (US)
Pages (from-to)60-68
Number of pages9
JournalJournal of Reproductive Immunology
Volume126
DOIs
StatePublished - Apr 1 2018

Fingerprint

Extraembryonic Membranes
Membrane Potentials
Interleukin-6
Gardnerella vaginalis
Mycoplasma
Cytokine Receptor gp130
Premature Birth
Immunohistochemistry
Mycoplasma hominis
Ureaplasma urealyticum
Pregnancy Outcome
Conditioned Culture Medium
Infection
Immunoassay
Analysis of Variance
Hot Temperature
Biomarkers
Cytokines
Bacteria
Gene Expression

Keywords

  • Fetal membranes in vitro
  • Genital mycoplasmas
  • Interleukin-6
  • Polybacterial infection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Polybacterial stimulation suggests discrete IL-6/IL-6R signaling in human fetal membranes : Potential implications on IL-6 bioactivity. / Noda-Nicolau, Nathalia Mayumi; Polettini, Jossimara; da Silva, Márcia Guimarães; Peltier, Morgan R.; Menon, Ramkumar.

In: Journal of Reproductive Immunology, Vol. 126, 01.04.2018, p. 60-68.

Research output: Contribution to journalArticle

Noda-Nicolau, Nathalia Mayumi ; Polettini, Jossimara ; da Silva, Márcia Guimarães ; Peltier, Morgan R. ; Menon, Ramkumar. / Polybacterial stimulation suggests discrete IL-6/IL-6R signaling in human fetal membranes : Potential implications on IL-6 bioactivity. In: Journal of Reproductive Immunology. 2018 ; Vol. 126. pp. 60-68.
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AB - The polybacterial invasion of the amniotic cavity and risk of preterm birth is often due to cervicovaginal bacteria such as genital mycoplasmas (Mycoplasma hominis and Ureaplasma urealyticum) and Gardnerella vaginalis. The most studied biomarker associated with preterm birth is interleukin-6 (IL-6), a pleiotropic cytokine that performs different functions based on classical or trans-signaling mechanisms. This study evaluated the changes in IL-6 and IL-6 function associated accessory molecules by human fetal membranes to determine the functional availability of IL-6 assessment in an in vitro model of polybacterial infection. Fetal membranes were treated with LPS or heat-inactivated genital mycoplasmas and G. vaginalis alone or in combination. IL-6 and its soluble receptors (sgp130, sIL-6R) were assessed in conditioned medium by immunoassays and membrane-bound receptors were evaluated in the tissue using immunohistochemistry and RT-PCR. Data from protein and gene expression were evaluated using linear mixed effects models. Data from immunohistochemistry were evaluated using one-way analysis of variance followed by the Tukey test. Genital mycoplasmas alone, or in combination, inhibited IL-6 trans-signaling with increased sgp130 production. G. vaginalis activated the classical IL-6 signaling pathway, as did LPS. Polybacterial treatment resulted in a balanced response with neither pathway being favored. The increase in IL-6 production by fetal membranes in response to infection is likely a non-specific innate response and not an indicator of a functional mediator of any labor-inducing pathways. This suggests that correlating the risk of adverse pregnancy outcomes and designing interventions based on IL-6 levels without considering soluble receptors may be an ineffective strategy.

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