Obese pregnant women develop severe insulin resistance and enhanced systemic and placental inflammation, suggesting associated modifications of endocrine and immune functions. Activation of innate immunity by endotoxins/lipopolysaccharides (LPS) has been proposed as a mechanism for enhancing metabolic alterations in disorders with insulin resistance. The aim of this study was to characterize the immune responses developed by the adipose tissue AT and their potential links to maternal endotoxemia in pregnancy with obesity. Blood and subcutaneous abdominal AT were obtained from 120 lean and obese women (term pregnancy) recruited at delivery. Gene expression was assessed in AT and stromal vascular cells isolated from a subset of 24 subjects from the same cohort. Doubling of plasma endotoxin concentrations indicated subclinical endotoxemia in obese compared with lean women. This was associated with significant increase in systemic CRP and IL-6 but not TNF-alpha concentrations. AT inflammation was characterized by accumulation of CD68+ macrophages with a 3-fold increased gene expression of the macrophage markers CD68, EMR1 and CD14. Gene expression for cytokines IL-6, TNF-α, IL-8, and MCP1 and for LPS - sensing CD14, TLR4, TRAM2 was 2.5-5 fold higher in stromal cells of obese compared to lean. LPS-treated cultured stromal cells of obese women expressed a 5-16 fold stimulation of the same cytokines up-regulated in vivo. Our data demonstrate that subclinical endotoxemia is associated with systemic and AT inflammation in obese pregnant women. Recognition of bacterial pathogens may contribute to the combined dysfunction of innate immunity and the metabolic systems in AT.
Objective
To characterize immune modulation as expressed by cytokine assays at three time-points in human pregnancy.
Study Design
This is a prospective, longitudinal study of a broad panel of cytokine expression during singleton pregnancies resulting in an uncomplicated, full-term, live births. Peripheral blood was obtained at 8–14, 18–22, and 28–32 weeks gestation. Six cytokines—IFN-γ, IL-4, TNF-α, IL-1β, IL-6, and IL-10—were measured in supernatants obtained from whole blood stimulations with PHA or LPS and were compared to unstimulated controls. Samples were processed by Luminex-100 MAP®. We used Generalized Linear Models (GLM) to evaluate cytokine trajectories.
Results
Complete data were obtained for forty-five uncomplicated pregnancies. Overall, peripheral blood WBC’s demonstrated dampened cytokine responses. However, over the course of pregnancy, we found enhanced counter-regulatory cytokine expression (e.g., shown by increased IL-10).
Conclusion
The overall decrease in pro-inflammatory cytokines and increase in counter-regulatory cytokines as uncomplicated pregnancy progresses supports the evolving concepts of immunoregulation for the maintenance of a viable pregnancy.
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