Progesterone Is Essential for Protecting against LPS-Induced Pregnancy Loss. LIF as a Potential Mediator of the Anti-inflammatory Effect of Progesterone

Abstract

Lipopolysaccharide (LPS) administration to mice on day 7 of gestation led to 100% embryonic resorption after 24 h. In this model, nitric oxide is fundamental for the resorption process. Progesterone may be responsible, at least in part, for a Th2 switch in the feto-maternal interface, inducing active immune tolerance against fetal antigens. Th2 cells promote the development of T cells, producing leukemia inhibitory factor (LIF), which seems to be important due to its immunomodulatory action during early pregnancy. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced embryonic resorption, and whether LIF can mediate hormonal action. Using in vivo and in vitro models, we provide evidence that circulating progesterone is an important component of the process by which infection causes embryonic resorption in mice. Also, LIF seems to be a mediator of the progesterone effect under inflammatory conditions. We found that serum progesterone fell to very low levels after 24 h of LPS exposure. Moreover, progesterone supplementation prevented embryonic resorption and LPS-induced increase of uterine nitric oxide levels in vivo. Results show that LPS diminished the expression of the nuclear progesterone receptor in the uterus after 6 and 12 h of treatment. We investigated the expression of LIF in uterine tissue from pregnant mice and found that progesterone up-regulates LIF mRNA expression in vitro. We observed that LIF was able to modulate the levels of nitric oxide induced by LPS in vitro, suggesting that it could be a potential mediator of the inflammatory action of progesterone. Our observations support the view that progesterone plays a critical role in a successful pregnancy as an anti-inflammatory agent, and that it could have possible therapeutic applications in the prevention of early reproductive failure associated with inflammatory disorders.

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…26 In the uterus of pregnant mice, LIF likely plays a similar but local role in the protective effect of progesterone against endotoxin-induced fetal demise by reducing nitric oxide levels in utero. 27 Another important gestational factor is IL-10, which is a type-2 cytokine that is expected to play a key role in pregnancy immunotolerance through the establishment of a Th2 immune response at the maternal2fetal interface. 28,29 IL-10 inhibits the production of several pro-inflammatory cytokines, including TNF-a in Mws and IFN-c in NK cells, thereby preventing the development of type-1 immune reactions that are deleterious for both the establishment and maintenance of pregnancy.…”

Effect of molecular hydrogen on uterine inflammation during preterm labour

“…However, while the underlying molecular mechanisms are not fully understood, maternal plasma progesterone has been reported to be lower in LPS-induced preterm birth models (19), and unaltered by probiotics (20). H 2 may therefore be superior in this regard, as a previous study reported that progesterone exerted anti-inflammatory effects at the maternal-foetal interface and increased the proportion of decidual regulatory T cells (21).…”

Progestogens in Infertility Practice

“…Progesterone up regulates LIF mRNA expression in vitro [ 20 ]. Progesterone inhibits NK activity at the feto-maternal interface, inhibits the release of arachidonic acid, and favours the production of asymmetric, pregnancy-protecting antibodies.…”