Cyclic AMP in human preterm infant blood is associated with increased TLR-mediated production of acute-phase and anti-inflammatory cytokines in vitro

Strunk, Tobias; Haren, Simon D. van; Hibbert, Julie; Pettengill, Matthew A.; Ozonoff, Al; Jans, Jop; Schüller, Simone; Burgner, David; Levy, Ofer; Currie, Andrew

doi:10.1038/s41390-019-0586-2

Cited by 11 publications

(10 citation statements)

References 36 publications

(46 reference statements)

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“…First of all, we found that tissue cAMP content was significantly higher in placentas from female newborns compared to males. Supporting our findings, previous studies have found higher cAMP levels in cord blood of female neonates, 37,42 as well as increased placental expression and maternal serum levels of hCG, a cAMP‐inducible hormone, in female‐carrying pregnancies 42–44 . Although hCG is mainly stimulated by cAMP, an interplay between hCG and cytokines has been reported 45–47 .…”

Section: Discussionsupporting

confidence: 91%

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Placentas associated with female neonates from pregnancies complicated by urinary tract infections have higher cAMP content and cytokines expression than males

Olmos-Ortíz¹,

Olivares-Huerta²,

García-Quiroz³

et al. 2021

American J Rep Immunol

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Problem The cAMP pathway is involved in important biological processes including immune regulation and hormone signaling. At the feto‐maternal unit, cAMP participates in placental function/physiology and the establishment of immunoendocrine networks. Low cAMP in male fetuses cord blood has been linked to poorer perinatal outcomes; however, cAMP placental content and its relationship with immune factors and fetal sex in an infectious condition have not been investigated. Method of study Sex‐dependent changes in cAMP content and its association with cytokines and antimicrobial peptides expression were studied in human placentas collected from normal pregnancies and with urinary tract infections (UTI). Radioimmunoassay was used to quantify cAMP in placental tissue, while immune markers expression was studied by qPCR. Additionally, cAMP effect on antimicrobial peptides expression was studied in cultured trophoblasts challenged with lipopolysaccharide, to mimic an infection. Results In UTI, placentas from female neonates had higher cAMP tissue content and increased expression of TNFA, IL1B, and IL10 than those from males, where IFNG was more elevated. While cAMP negatively correlated with maternal bacteriuria and IFNG, it positively correlated with the antimicrobial peptide S100A9 expression in a sex‐specific fashion. In cultured trophoblasts, cAMP significantly stimulated β‐defensin‐1 while reduced the lipopolysaccharide‐dependent stimulatory effect on β‐defensin‐2, β‐defensins‐3, and S100A9. Conclusion Our results showed higher cAMP content and defense cytokines expression in placentas associated with female neonates from pregnancies complicated by UTI. The associations between cAMP and bacteriuria/immune markers, together with cAMP’s ability to differentially regulate placental antimicrobial peptides expression, suggest a dual modulatory role for cAMP in placental immunity.

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Section: Discussionsupporting

confidence: 91%

“…On the other hand, while IL1B is superinduced by cAMP in the presence of LPS, 12 IFNG , and TNFA are known to be inhibited 6–8 . Also important in the context of our study, LPS, which is a component of bacterial wall, has been shown to stimulate TNFA, IL1B, and IL10 levels in cord blood 37 …”

Section: Methodsmentioning

confidence: 58%

Placentas associated with female neonates from pregnancies complicated by urinary tract infections have higher cAMP content and cytokines expression than males

Olmos-Ortíz¹,

Olivares-Huerta²,

García-Quiroz³

et al. 2021

American J Rep Immunol

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“…Whole-blood samples (25 μL) were surface-stained for 15 min with leukocyte monoclonal mouse anti-human antibodies, as recently described [14]. Briefly, cells were incubated with allophycocyanin-H7-conjugated CD16 (clone 3G8) and AmCyan-conjugated CD45 (clone 2D1), purchased from BD Biosciences.…”

Section: Methodsmentioning

confidence: 99%

Lactoferrin Expression Is Not Associated with Late-Onset Sepsis in Very Preterm Infants

et al. 2020

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Background: Preterm infants are at a high risk of developing late-onset sepsis (LOS). Lactoferrin is one of the most abundant endogenous antimicrobial proteins expressed in breast milk, stools, and blood, and a candidate for preventive intervention. Large clinical trials have recently investigated whether enteral supplementation with bovine lactoferrin reduces LOS. Aim: To characterize lactoferrin levels in preterm infants with and without LOS during the first month of life. Methods: Very preterm and term infants were recruited and serial biosamples collected during the first month of life. Lactoferrin levels were determined by immunoassay in cord blood and peripheral blood on days 1, 7, 14, 21, and 28; in the stools on days 1 and 28; and in the mother’s breast milk on days 7 and 21. Furthermore, we assessed the capacity of the peripheral blood to release lactoferrin in response to an in vitro challenge with live Staphylococcus epidermidis, lipopolysaccharide, and fibroblast-stimulating lipopeptide 1. Results: Plasma lactoferrin levels were higher in cord blood and day 1 peripheral blood and declined during the first month of life. Plasma lactoferrin levels were similar in term infants and in preterm infants with (n = 32) and without LOS (n = 53). S. epidermidis-induced lactoferrin levels were lower following the sepsis episode. Conclusions: Endogenous lactoferrin expression in preterm infants does not appear to affect their risk of developing LOS. These findings are in line with the lack of benefit recently observed in large trials of enteral supplementation with bovine lactoferrin to prevent LOS.

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“…A recent report demonstrated that human fetal membranes and neutrophils that interact directly, and LPS-stimulated factors originating from the fetal membrane, can effectively recruit, and trigger neutrophils to induce inflammatory cytokines and helps them build neutrophil extracellular traps. The effect of TLR activation in preterm infants has also been studied by checking the level of the immunomodulatory factor, such as cAMP concentration in cord blood samples along with peripheral blood samples of preterm babies for the first month after delivery (57).…”

Section: Fetal Membranesmentioning

confidence: 99%

Insight Into TLR4-Mediated Immunomodulation in Normal Pregnancy and Related Disorders

2020

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Unlike organ transplants where an immunosuppressive environment is required, a successful pregnancy involves an extremely robust, dynamic, and responsive maternal immune system to maintain the development of the fetus. A specific set of hormones and cytokines are associated with a particular stage of pregnancy. Any disturbance that alters this fine balance could compromise the development and function of the placenta. Although there are numerous underlying causes of pregnancy-related complications, untimely activation of Toll-like receptors (TLR), primarily TLR4, by intrauterine microbes poses the greatest risk. TLR4 is an important Pattern Recognition Receptor (PRR), which activates both innate and adaptive immune cells. TLR4 activation by LPS or DAMPs leads to the production of pro-inflammatory cytokines via the MyD88 dependent or independent pathway. Immune cells modulate the materno-fetal interface by TLR4-mediated cytokine production, which changes at different stages of pregnancy. In most pregnancy disorders, such as PTB, PE, or placental malaria, the TLR4 expression is upregulated in immune cells or in maternal derived cells, leading to the aberrant production of pro-inflammatory cytokines at the materno-fetal interface. Lack of functional TLR4 in mice has reduced the pro-inflammatory responses, leading to an improved pregnancy, which further strengthens the fact that abnormal TLR4 activation creates a hostile environment for the developing fetus. A recent study proposed that endothelial and perivascular stromal cells should interact with each other in order to maintain a homeostatic balance during TLR4-mediated inflammation. It has been reported that depleting immune cells or supplying anti-inflammatory cytokines can prevent PTB, PE, or fetal death. Blocking TLR4 signaling or its downstream molecule by inhibitors or antagonists has proven to improve pregnancy-related complications to some extent in clinical and animal models. To date, there has been a lack of knowledge regarding whether TLR4 accessories such as CD14 and MD-2 are important in pregnancy and whether these accessory molecules could be promising drug targets for combinatorial treatment of various pregnancy disorders. This review mainly focuses on the activation of TLR4 during pregnancy, its immunomodulatory functions, and the upcoming advancement in this field regarding the improvement of pregnancy-related issues by various therapeutic approaches.

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Cyclic AMP in human preterm infant blood is associated with increased TLR-mediated production of acute-phase and anti-inflammatory cytokines in vitro

Cited by 11 publications

References 36 publications

Placentas associated with female neonates from pregnancies complicated by urinary tract infections have higher cAMP content and cytokines expression than males

Placentas associated with female neonates from pregnancies complicated by urinary tract infections have higher cAMP content and cytokines expression than males

Lactoferrin Expression Is Not Associated with Late-Onset Sepsis in Very Preterm Infants

Insight Into TLR4-Mediated Immunomodulation in Normal Pregnancy and Related Disorders

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