Interleukin-33 in the human placenta

Topping, Vanessa; Romero, Roberto; Than, Nándor Gábor; Tarca, Adi L.; Kim, Sun Young; Wang, Bing; Yeo, Lami; Kim, Chong Jai; Hassan, Sonia S.; Kim, Jung Sun

doi:10.3109/14767058.2012.735724

Cited by 28 publications

(29 citation statements)

References 151 publications

(168 reference statements)

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“…Indeed, it has been demonstrated that pro-inflammatory cytokines are increased in the plasma or serum of women with early-onset preeclampsia [35,41,42] and severe preeclampsia [36,40,41] when compared to women with uncomplicated pregnancies. Moreover, IL-1b or TNF-a (pro-inflammatory cytokines which are increased in preeclampsia) are able to stimulate vascular endothelial cells to secrete sST2 into supernatant [146,147]. This hypothesis is also consistent with the view that preeclampsia is characterized by a Th1/Th2 imbalance towards a Th1 type immune response [160,161,171], since sST2 can inhibit IL-33 function, thus favoring a shift toward a Th1 response.…”

Section: Plasma Concentrations Of Soluble St2 Is Elevated In Preeclamsupporting

confidence: 75%

“…In contrast, sST2 acts as a decoy receptor for IL-33 and is thought to inhibit IL-33 function, thus favoring a shift toward the Th1 immune response [145]. Moreover, sST2 can be secreted in response to inflammatory signals by endothelial cells [146,147]. The involvement of sST2 has been observed in a variety of pathological conditions characterized by: (1) intravascular inflammation [145,[148][149][150][151] (i.e.…”

Section: Introductionmentioning

confidence: 99%

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Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

Stampalija

Chaiworapongsa

Romero

et al. 2013

The Journal of Maternal-Fetal & Neonatal Medicine

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Objectives: Angiogenic/anti-angiogenic factors have emerged as one of the promising biomarkers for the prediction of preeclampsia. Since not all patients with preeclampsia can be identified by these analytes, the search for additional biomarkers continues. The soluble form of ST2 (sST2), a protein capable of binding to interleukin (IL)-33 and thus contributing to a Th1-biased immune response, has been reported to be elevated in maternal plasma of women with preeclampsia. The aims of this study were to examine: (1) differences in maternal plasma concentrations of sST2 and IL-33 between women diagnosed with preeclampsia and those having uncomplicated pregnancies; (2) the relationship between sST2, umbilical and uterine artery Doppler velocimetry, and the severity of preeclampsia; and (3) the performance of sST2 and angiogenic/anti-angiogenic factors in identifying patients with preeclampsia at the time of diagnosis. Methods: This cross-sectional study included women with preeclampsia (n ¼ 106) and women with an uncomplicated pregnancy (n ¼ 131). Plasma concentrations of sST2, IL-33, soluble vascular endothelial growth factor receptor (sVEGFR)-1, soluble endoglin (sEng) and placental growth factor (PlGF) were determined by enzyme linked immune sorbent assay. Area under the receiver operating characteristic curve (AUC) for the identification of preeclampsia was examined for each analyte. Results: (1) Patients with preeclampsia had a higher mean plasma concentrations of sST2 than those with an uncomplicated pregnancy (p50.0001), while no significant difference in the mean plasma concentration of IL-33 between the two groups was observed; (2) the magnitude of this difference was greater in early-onset, compared to late-onset disease, and in severe compared to mild preeclampsia; (3) sST2 plasma concentrations did not correlate with the results of uterine or umbilical artery Doppler velocimetry (p ¼ 0.7 and p ¼ 1, respectively) among women with preeclampsia; (4) sST2 correlated positively with plasma concentrations of sVEGFR1-1 and sEng (Spearman's Rho ¼ 0.72 and 0.63; each p50.0001), and negatively with PlGF (Spearman's Rho ¼ À0.56, p50.0001); and (5) while the AUC achieved by sST2 and angiogenic/anti-angiogenic factors in identifying women with preeclampsia at the time of diagnosis were non-significantly different prior to term (537 weeks of gestation), thereafter the AUC achieved by sST2 was significantly less than that achieved by angiogenic/anti-angiogenic factors. Conclusions: Preeclampsia is associated with increased maternal plasma concentrations of sST2. The findings that sST2 concentrations do not correlate with uterine or umbilical artery Doppler velocimetry in women with preeclampsia suggest that elevated maternal plasma sST2 concentrations in preeclampsia are not related to the increased impedance to flow in the uteroplacental circulation. The performance of sST2 in identifying preeclampsia at the time of diagnosis prior to 37 weeks of gestation was comparable to that of angiogenic/anti-angiogenic f...

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Section: Plasma Concentrations Of Soluble St2 Is Elevated In Preeclamsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

Stampalija

Chaiworapongsa

Romero

et al. 2013

The Journal of Maternal-Fetal & Neonatal Medicine

Self Cite

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“…Addition of rhu IL-1b further increased IL-33 levels in the culture medium, pointing to paracrine regulation of IL-33 secretion in vivo, as vCTBs were shown to release IL-1b (55). Despite detectable IL-33 serum concentrations in pregnant women, a recent study reports the absence of IL-33 in third-trimester placental explant supernatants or placental perfusates (56). In our study, our findings might provide several explanations for the authors' unfruitful attempts to verify secreted placenta-derived IL-33.…”

Section: Discussioncontrasting

confidence: 45%

Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth

Fock

Mairhofer

Otti

et al. 2013

The Journal of Immunology

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IL-33, the most recently discovered member of the IL-1 superfamily and ligand for the transmembrane form of ST2 (ST2L), has been linked to several human pathologies including rheumatoid arthritis, asthma, and cardiovascular disease. Deregulated levels of soluble ST2, the natural IL-33 inhibitor, have been reported in sera of preeclamptic patients. However, the role of IL-33 during healthy pregnancy remains elusive. In the current study, IL-33 was detected in the culture supernatants of human placental and decidual macrophages, identifying them as a major source of secreted IL-33 in the uteroplacental unit. Because flow cytometry and immunofluorescence stainings revealed membranous ST2L expression on specific trophoblast populations, we hypothesized that IL-33 stimulates trophoblasts in a paracrine manner. Indeed, BrdU incorporation assays revealed that recombinant human IL-33 significantly increased proliferation of primary trophoblasts as well as of villous cytotrophoblasts and cell column trophoblasts in placental explant cultures. These effects were fully abolished upon addition of soluble ST2. Interestingly, Western blot and immunofluorescence analyses demonstrated that IL-33 activates AKT and ERK1/2 in primary trophoblasts and placental explants. Inhibitors against PI3K (LY294002) and MEK1/2 (UO126) efficiently blocked IL-33–induced proliferation in all model systems used. In summary, with IL-33, we define for the first time, to our knowledge, a macrophage-derived regulator of placental growth during early pregnancy.

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“…In contrast, among women with PTL, those with IAI had a lower median amniotic fluid sST2 concentration than those without IAI [152]. Interestingly, IL-33 expression was also found in macrophages of the chorioamniotic membranes in acute chorioamnionitis [153]. …”

Section: Introductionmentioning

confidence: 99%

Soluble ST2 in the fetal inflammatory response syndrome:in vivoevidence of activation of the anti-inflammatory limb of the immune response

Stampalija

Romero

Korzeniewski

et al. 2013

The Journal of Maternal-Fetal & Neonatal Medicine

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Objective Inflammation is a mechanism of host response to infection which can be harmful when inappropriately modulated. Soluble ST2 (sST2) is a decoy receptor of interleukin (IL)-33, and this complex modulates the balance in the Th1/Th2 immune response. Moreover, sST2 inhibits the production of pro-inflammatory cytokines in cooperation with an anti-inflammatory cytokine, IL-10. The objectives of this study were to: 1) determine whether umbilical cord plasma sST2 concentration differ between comparing preterm neonates with and without funisitis and between those with and without the fetal inflammatory response syndrome (FIRS); and 2) evaluate the relationship between sST2 and IL-10 among neonates with funisitis and/or FIRS. Methods Umbilical cord plasma was collected from neonates delivered prematurely due to preterm labor or preterm prelabor rupture of membranes with (n=36), and without funisitis (n=30). FIRS (umbilical cord IL-6 concentration ≥17.5 pg/mL) was identified in 29 neonates. Plasma sST2 and IL-10 concentrations were determined by ELISA. Results The median umbilical cord plasma sST2 concentration was 6.7-fold higher in neonates with FIRS than in those without FIRS (median 44.6 ng/mL, interquartile range [IQR] 13.8–80.3 ng/mL vs. median 6.7 ng/mL, IQR 5.6–20.1 ng/mL; p<0.0001). Similarly, the median umbilical cord plasma sST2 concentration was 2.6-fold higher in neonates with funisitis than in those without funisitis (median 19.1 ng/mL; IQR 7.1–75.0 ng/mL vs. median 7.2 ng/mL; IQR 5.9–23.1 ng/mL; p=0.008). There was a strong positive correlation between sST2 and IL-10 in neonates with funisitis and/or FIRS (Spearman’s Rho=0.7, p<0.0001). Conclusions FIRS and funisitis are associated with an elevation of umbilical cord plasma concentrations of soluble ST2. This protein represents an important mediator of the immune response in neonates diagnosed with fetal inflammatory response syndrome by promoting an anti-inflammatory effect in association with IL-10.

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Interleukin-33 in the human placenta

Cited by 28 publications

References 151 publications

Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia

Macrophage-Derived IL-33 Is a Critical Factor for Placental Growth

Soluble ST2 in the fetal inflammatory response syndrome:in vivoevidence of activation of the anti-inflammatory limb of the immune response

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