Evidence of perturbations of the cytokine network in preterm labor

Abstract

Objective Intra-amniotic infection/inflammation is the only mechanism of disease with persuasive evidence of causality for spontaneous preterm labor/delivery. Previous studies about the behavior of cytokines in preterm labor have been largely based on the analysis of the behavior of each protein independently. Emerging evidence indicates that the study of biological networks can provide insight into the pathobiology of disease, and improve biomarker discovery. The goal of this study is to characterize the inflammatory-related proteins network in the amniotic fluid in patients with preterm labor. Materials and Methods A retrospective cohort study was conducted, and included women with singleton pregnancies who presented with spontaneous preterm labor and intact membranes (n=135). These patients were classified according to the results of amniotic fluid culture, broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS), and amniotic fluid concentration of interleukin (IL)-6 into the following groups: 1) those without intra-amniotic inflammation (n=85); 2) those with microbial-associated intra-amniotic inflammation (n=15); and 3) those with intra-amniotic inflammation without detectable bacteria (n=35). Amniotic fluid concentrations of 33 inflammatory-related proteins were determined using a multiplex bead array assay. Results 1) Patients with preterm labor and intact membranes who had microbial-associated intra-amniotic inflammation had a higher amniotic fluid inflammatory-related protein concentration correlation than those without intra-amniotic inflammation (113 perturbed correlations). IL-1β, IL-6, MIP-1α, and IL-1α were the most connected nodes (highest degree) in this differential correlation network (degree of 20, 16, 12, and 12, respectively); 2) patients with sterile intra-amniotic inflammation had correlation patterns of inflammatory-related proteins that were both increased and decreased when compared to those without intra-amniotic inflammation (50 perturbed correlations). IL-1α, MIP-1α, and IL-1β were the most connected nodes in this differential correlation network (degrees of 12, 10, and 7, respectively); and 3) there were more coordinated inflammatory-related protein concentrations in the amniotic fluid of women with microbial-associated intra-amniotic inflammation than in those with sterile intra-amniotic inflammation (60 perturbed correlations), with IL-4 and IL-33 having the largest number of perturbed correlations (degree of 15 and 13, respectively). Conclusion We report for the first time an analysis of the inflammatory-related protein network in spontaneous preterm labor. Patients with preterm labor who had microbial-associated intra-amniotic inflammation had more coordinated amniotic fluid inflammatory-related proteins than either those with sterile intra-amniotic inflammation or those without intra-amniotic inflammation. The correlations were also stronger in patients with sterile intra-amniotic inflammation than in those without intra-...

Lipopolysaccharide‐induced maternal inflammation induces direct placental injury without alteration in placental blood flow and induces a secondary fetal intestinal injury that persists into adulthood

“…A histologic scoring system was developed based on prior studies 9 to quantify the degree of placental mineralization and necrosis (Figure 4A, C). Placental tissue exposed to LPS had significantly higher scores for mineralization, most significantly within the spongiotrophoblastic layer ( P = .001; LPS n = 8, Sham n = 10) (Figure 4B, D).…”

“…7,8 Activation of the innate immune system results in downstream synthesis of pro-inflammatory cytokines and chemokines, 9 with the most significant elevations seen in IL-6, IL-8, IL-1β, TNF, and macrophage inflammatory proteins. 9,10 In severe cases, maternal infection can elicit fetal inflammatory response syndrome (FIRS), which is defined as a fetal plasma concentration of IL-6 >11 pg/mL, 11 or result in development of preterm labor. 12 Neonates who are diagnosed with FIRS have an increased risk for severe neonatal morbidity.…”

Myometrial cytokines and their role in the onset of labour

“…The rise in AF IL-6 precedes that of IL-8, suggesting that IL-6 has a role in the initiation of the inflammatory cascade required for the onset of labour (Kemp et al 2002a,b). Recent work by Romero and coworkers have shown varying cytokine networks noted in the AF associated with PTL with intact membranes and intra-amniotic inflammation (both microbial and sterile) (Romero et al 2015). Interestingly, the chemokine CCL-20, which targets immature dendritic cells, effector/ memory T cells and B lymphocytes increases in AF with advancing gestational age.…”

“…With the onset of TL, there are increased concentrations of IL-1β and TNF-α in AF (Romero et al 1990, Laham et al 1993). IL-6 has been noted to be raised in AF in women with spontaneous labour (Andrews et al 1995) and particularly raised in PTL associated with intraamniotic infection; and even considered a predictor for PTL before 34 weeks gestation (Chaemsaithong et al 2015). IL-8 concentrations in AF increase progressively from early pregnancy to term and more markedly with the onset of spontaneous TL (Romero et al 1991, Saito et al 1993, Laham et al 1994.…”

The Use of New Technologies in the Study of Pregnancy Disorders: The OMICS Approach

“…reported for the fi rst time the analysis of the infl ammatoryrelated protein network in the amniotic fl uid of patients with spontaneous preterm labor and intact membranes [13]. Little is known about the overall metabolic status of the term and preterm neonate.…”