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.
Highlights
Maternal infection is one of the main causes of spontaneous abortion in humans [1]
Effect of LPS Treatment on Serum Progesterone Levels Considering that there is a close relationship between the amount of circulating progesterone and an ongoing pregnancy, we investigated whether LPS administration could change serum progesterone levels
The treatment led to a remarkable decline of 60% in serum progesterone after both 12 and 24 h, compared with levels in controls harvested at the same time (Figure 1)
Summary
Maternal infection is one of the main causes of spontaneous abortion in humans [1]. In rodents, infection has been associated with an adverse developmental outcome, including embryonic resorption, intrauterine fetal death, intrauterine growth retardation and preterm delivery [2], [3], [4]. Systemic LPS circulation elicits a series of signal transduction events that culminate in the release of numerous biochemical mediators, including cytokines, arachidonic acid metabolites, nitric oxide and toxic O2 radicals, among others [5]. Several of these cytokines have been involved in the delicate immune system balance that exists within the feto-maternal interface. We have previously developed a murine model to study the mechanisms of LPS-induced embryonic resorption. Intraperitoneal administration of 1 mg of LPS per gram of body weight on day 7 of gestation produced 100% embryonic resorption at 24 h and expulsion of the resorbed fetus within the 24 h [3], [4]
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