Estradiol and Progesterone Strongly Inhibit the Innate Immune Response of Mononuclear Cells in Newborns

Abstract

Newborns are particularly susceptible to bacterial infections due to qualitative and quantitative deficiencies of the neonatal innate immune system. However, the mechanisms underlying these deficiencies are poorly understood. Given that fetuses are exposed to high concentrations of estradiol and progesterone during gestation and at time of delivery, we analyzed the effects of these hormones on the response of neonatal innate immune cells to endotoxin, bacterial lipopeptide, and Escherichia coli and group B Streptococcus, the two most common causes of early-onset neonatal sepsis. Here we show that at concentrations present in umbilical cord blood, estradiol and progesterone are as powerful as hydrocortisone for inhibition of cytokine production by cord blood mononuclear cells (CBMCs) and newborn monocytes. Interestingly, CBMCs and newborn monocytes are more sensitive to the effects of estradiol and progesterone than adult peripheral blood mononuclear cells and monocytes. This increased sensitivity is associated with higher expression levels of estrogen and membrane progesterone receptors but is independent of a downregulation of Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response gene 88 in newborn cells. Estradiol and progesterone mediate their anti-inflammatory activity through inhibition of the NF-B pathway but not the mitogenactivated protein kinase pathway in CBMCs. Altogether, these results suggest that elevated umbilical cord blood concentrations of estradiol and progesterone acting on mononuclear cells expressing high levels of steroid receptors contribute to impair innate immune responses in newborns. Therefore, intrauterine exposure to estradiol and progesterone may participate in increasing susceptibility to infection during the neonatal period.Newborns are at high risk of severe bacterial infections. Early-onset neonatal sepsis occurs during the first week of life in 1 to 5 per 1,000 births (14,24,25). Group B Streptococcus (GBS) and Escherichia coli are involved in more than 50% of episodes of early-onset neonatal sepsis. Despite antimicrobial therapy and improvements in neonatal intensive care, the mortality due to neonatal sepsis remains high (5 to 15%) and survivors are at risk of permanent neurologic damage (14,24,25). The particularly high susceptibility to infection during the neonatal period has been associated with quantitative and qualitative deficiencies of innate immunity (such as reduced levels of opsonins, decreased cytokine production, and impaired function of phagocytes) and adaptive immunity (such as impaired function of antigen-presenting cells and T cells and decreased production of immunoglobulins) (1,19,36). Although the differences between the neonatal and adult immune responses are relatively well described, the underlying mechanisms that account for the decreased ability of newborns to mount efficient immune responses remain largely unknown.Fetuses are chronically exposed to high levels of steroid hormones due to placental production. Concentrations ...

High expression levels of macrophage migration inhibitory factor sustain the innate immune responses of neonates

“…In contrast, E. coli leads to the secretion of much higher levels of TNF and IL-6 than GBS ( Fig. S2 A and B) (10), in agreement with the concept that MIF production is regulated differently than the production of classical proinflammatory cytokines (30,31). Of note, 24-h exposure to LPS increased MIF release 1.3-fold without affecting the intracellular MIF pool in newborn monocytes.…”

“…This suggests that whole microorganisms are more powerful than pure microbial products at inducing MIF release by monocytes. Estradiol, progesterone, and cortisol are present at high concentrations in the fetal and neonatal circulation (10). Exposure of newborn monocytes to estradiol, progesterone, and hydrocortisone at concentrations similar to those observed in the circulation at birth increased MIF secretion, implying that these hormones could participate in maintaining high levels of MIF in newborns (Fig.…”

“…Notably, adenosine, prostaglandins, cortisol, estradiol, and progesterone are present at high circulating concentrations perinatally and have the ability to reduce the production of proinflammatory cytokines by neonatal innate immune cells exposed to microbial products (9)(10)(11)(12)(13). Fetal exposure to antiinflammatory mediators may be advantageous in utero to maintain tolerance to maternal antigens, to avoid powerful proinflammatory responses that can lead to preterm delivery and damage-developing organs, and to establish tolerance to colonizing microorganisms immediately after birth (3,14).…”

Le facteur d’inhibition de la migration des macrophages (MIF), un régulateur de la réponse immunitaire innée néonatale

“…Ces molécules diffusent dans la circulation foetale et influencent le système immunitaire du foetus et du nouveau-né. En effet, l'oestradiol et la progestérone inhibent l'activation de la voie de signalisation NF-B (nuclear factor-kappa B) ainsi que la production de TNF- (facteur de nécrose tumorale alpha) et d'IL(interleukine)-6 par des monocytes exposés à des bactéries coliformes [6]. L'adénosine et les prostaglandines PGE 2 et PGF 2 sécrétées par le placenta sont également présentes à des concentrations élevées dans la circulation Pendant la grossesse, le placenta (en rouge) produit en abondance des hormones stéroïdiennes, de l'adénosine et des prostaglandines (dont PGE 2 ) qui gagnent la circulation foetale par l'intermédiaire de la veine ombilicale (flèche jaune).…”

Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates

“…5,6 NK cells are broadly reactive against different kinds of virus, such as influenza virus, herpes viruses, hepatitis B virus and Marburg virus, indicating a general role of the cells in antiviral immune responses. [6][7][8] Antiviral cytokine expression is a main mechanism to inhibit virus replication and eliminate virus. Previous studies have demonstrated that NK cells from the peripheral blood had obvious secretion of interferon (IFN)-c and tumor-necrosis factor (TNF)-a against virus but low response in appropriate-for-gestational-age (AGA) neonates.…”