Soluble ST2, a modulator of the inflammatory response, in preterm and term labor

Abstract

Objective Intra-amniotic infection/inflammation (IAI) is causally linked with spontaneous preterm labor and delivery. The ST2L receptor and its soluble form (sST2) are capable of binding to interleukin (IL)-33, a member of the IL-1 superfamily. Members of this cytokine family have been implicated in the onset of spontaneous preterm labor in the context of infection. Soluble ST2 has anti-inflammatory properties, and plasma concentrations are elevated in systemic inflammation, such as sepsis, acute pyelonephritis in pregnancy and the fetal inflammatory response syndrome. The aims of this study were to examine: 1) whether amniotic fluid concentrations of sST2 change with IAI, preterm, and term parturition; and 2) if mRNA expression of ST2 in the chorioamniotic membranes changes with acute histologic chorioamnionitis in women who deliver preterm. Methods A cross-sectional study was conducted to determine amniotic fluid concentrations of sST2 in: 1) women with preterm labor (PTL) who delivered at term (n=49); 2) women with PTL who delivered preterm without IAI (n=21); 3) women with PTL who delivered preterm with IAI (n=31); 4) term pregnancies not in labor (n=13); and 5) term pregnancies in labor (n=43). The amniotic fluid concentration of sST2 was determined by ELISA. The mRNA expression of ST2 in the chorioamniotic membranes of women who delivered preterm with (n=24), and without acute histologic chorioamnionitis (n=19) was determined by qRT-PCR. Results 1) Patients with PTL who delivered preterm with IAI had a lower median amniotic fluid concentration of sST2 compared to those with PTL who delivered preterm without IAI [median 410 ng/mL, inter-quartile range (IQR) 152-699 ng/mL vs. median 825 ng/mL, IQR 493-1216 ng/mL; p=0.0003] and those with PTL who delivered at term [median 410 ng/mL, IQR 152-699 ng/mL vs. median 673 ng/mL, IQR 468-1045ng/mL; p=0.0003]; 2) no significant differences in the median amniotic fluid concentration of sST2 were observed between patients with PTL who delivered at term and those who delivered preterm without IAI (p=0.4), and between women at term in labor and those at term not in labor (p=0.9); 3) the mean mRNA expression of ST2 was 4-fold lower in women who delivered preterm with acute histologic chorioamnionitis than in those without this lesion (p=0.008). Conclusions The median sST2 amniotic fluid concentration and mRNA expression of ST2 by chorioamniotic membranes is lower in PTL associated with IAI and acute histologic chorioamnionitis than in PTL without these conditions. Changes in the median amniotic fluid sST2 concentration are not observed in preterm and term parturition without IAI. Thus, amniotic fluid sST2 in the presence of IAI behaves differently when compared to sST2 in the plasma of individuals affected by fetal inflammatory response syndrome, acute pyelonephritis in pregnancy, and adult sepsis. Decreased concentrations of sST2 in IAI are likely to promote a pro-inflammatory response, which is important for parturition in the context of infection.

Evidence of perturbations of the cytokine network in preterm labor

“…Upon binding to ST2L, IL-33 is capable to produce Th2 associated cytokines 267-271 . We have previously reported that the median amniotic fluid soluble ST2 concentration and mRNA expression of ST2 in chorioamniotic membranes were lower in preterm labor with intra-amniotic infection and acute histologic chorioamnionitis than in those without these conditions, respectively 272 . Moreover, umbilical cord sST2 concentrations are 6.7 fold higher in neonates with FIRS than in those without FIRS 273 .…”

The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion*

“…Normal pregnancy is characterized by physiologic intravascular inflammation, demonstrated by a change in the immunophenotype of granulocytes and monocytes, and increased production of reactive oxygen species [82,83], as well as an increase in acute phase reactants during normal pregnancy (fibrinogen [84], C-reactive protein [85], etc.). In complications of pregnancy such as spontaneous preterm labor with intact membranes, [86–92], PPROM [93–98], preeclampsia [99–128], SGA [103,118,120,122,129–138], and pyelonephritis [83,139–141], intravascular inflammation is increased compared to normal pregnancy. These observations support the hypothesis that an exaggerated intravascular inflammatory response may play a role in the genesis of acute atherosis in the susceptible patient.…”

CXCL10 and IL‐6: Markers of two different forms of intra‐amniotic inflammation in preterm labor

“…This distinct form of intra‐amniotic inflammation differs from the intra‐amniotic inflammatory process observed in patients with preterm labor due to microbial invasion of the amniotic cavity (MIAC). Microorganisms and their products can induce a robust intra‐amniotic inflammatory response characterized by an elevation in amniotic fluid interleukin (IL)‐6 concentration, and neutrophil chemokines, such as IL‐8, as well as other inflammatory mediators capable of inducing the onset of labor . Recently, we provided an analysis of the protein inflammatory network for this condition .…”