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Polybacterial stimulation suggests discrete IL-6/IL-6R signaling in human fetal membranes: Potential implications on
Nathalia Mayumi Noda-Nicolau1, Jossimara Polettini2, Márcia Guimarães da Silva3
1Division of Maternal-Fetal Medicine and Perinatal Research, Department of Obstetrics and Gynecology, The University of Texas Medical Branch at Galveston, Galveston, TX, United States; Department of Pathology, Botucatu Medical School, UNESP - Univ. Estadual Paulista, Botucatu, São Paulo, Brazil.
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.
Insights
Interleukin-6 (IL-6) levels in fetal membranes during infection do not reliably predict preterm birth. Soluble receptors influence IL-6 signaling, making IL-6 alone an insufficient biomarker for adverse pregnancy outcomes.
Area of Science:
- Reproductive biology
- Immunology
- Microbiology
Background:
- Polybacterial infections, including genital mycoplasmas and Gardnerella vaginalis, are linked to preterm birth.
- Interleukin-6 (IL-6) is a key cytokine biomarker for preterm birth, acting through classical and trans-signaling pathways.
- The functional role of IL-6 in infection-induced preterm birth requires further investigation, particularly concerning its signaling accessory molecules.
Purpose of the Study:
- To investigate changes in IL-6 and its soluble receptors (sgp130, sIL-6R) in human fetal membranes under polybacterial infection conditions.
- To determine the functional availability of IL-6 signaling pathways in an in vitro model simulating amniotic cavity infection.
- To assess whether IL-6 levels alone are a reliable indicator of preterm birth risk.
Main Methods:
- Human fetal membranes were exposed to lipopolysaccharide (LPS), heat-inactivated genital mycoplasmas, and Gardnerella vaginalis, alone or in combination.
- IL-6 and soluble IL-6 receptors (sgp130, sIL-6R) in conditioned media were quantified using immunoassays.
- Membrane-bound IL-6 receptors and gene expression were analyzed via immunohistochemistry and RT-PCR.
- Statistical analysis included linear mixed effects models and one-way ANOVA with Tukey's test.
Main Results:
- Genital mycoplasmas inhibited IL-6 trans-signaling, evidenced by increased sgp130 production.
- Gardnerella vaginalis and LPS activated the classical IL-6 signaling pathway.
- Combined polybacterial treatment led to a balanced IL-6 signaling response, with neither pathway predominantly favored.
- Increased IL-6 production in fetal membranes appeared to be a non-specific innate immune response.
Conclusions:
- Elevated IL-6 levels in fetal membranes during infection may not directly mediate labor induction pathways.
- IL-6 trans-signaling inhibition by mycoplasmas and classical pathway activation by G. vaginalis suggest complex immune modulation.
- Relying solely on IL-6 levels to predict adverse pregnancy outcomes or design interventions may be ineffective without considering soluble receptor dynamics.
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