Revealing progesterone´s implications in early pregnancy loss induced by infection. LPS as a disrruptor of fetomaternal tolerance.

AISEMBERG JULIETA; FRANCHI ANA MARÍA

CABA

Congreso; 3rd Latin-american Symposium of Reproductive Immunology 2011.; 2011

Capítulo Latinoamericano (CLA) y Sociedad Americana de Inmunología de la Reproducción.

Lipopolysaccharide (LPS) from Gram-negative bacteria has been associated with adverse pregnancy outcome, such as embryonic resorption, intra-uterine fetal death and preterm delivery in rodents and humans. Endotoxin administration triggers a series of signal transduction events that conclude in release of numerous biochemical mediators as cytokines and nitric oxide (NO) among others. Several of these cytokines have been involved in the immune system balance that exists within the feto-maternal interface. However, the exact mechanism(s) of LPS-induced pregnancy loss remains unclear. Progesterone is indispensable in creating a suitable endometrial conditions for establishment and also for the maintenance of pregnancy. Besides its effects on the uterus, progesterone mediates interactions between endocine and immune systems, in order to protect the allogenic conceptus from immunological rejection. Progesterone may be in part responsible for a Th2 switch promoting the development of T cells producing Leukemia inhibitory factor (LIF), which seems to be important by its immunomodulatory action during early pregnancy. As well, LIF, like tumor necrosis factor alpha and interleukin-1, is involved in mediating aspects of the inflammatory response. We have already developed a mouse model to study the possible mechanisms of gram-negative bacterial LPS of inducing pregnancy loss. In our model, administration of 1ug/g (i.p.) of LPS on day 7 of pregnancy produced a 100% embryonic resorption (ER) at 24 h, with fetal expulsion at 48 h. This LPS dose produces systemic effects but it does not affect the survival of the mother. We have also demonstrated that NO plays an important role in ER. Our aim was to evaluate the involvement of progesterone in the mechanism of LPS-induced ER and LIF contribution as a mediator to 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 resorption in mice. In addition, LIF might be in part a mediator of progesterone effects. We observed that serum progesterone declines to very low levels by 12 and 24 h after LPS exposure and uterine progesterone receptor (PR) expression decreased significantly after 6 h of treatment. Progesterone pre-treatment prevented ER and blocked LPS–induced increase NO production in vivo. Progesterone incubation in uterine explants increased LIF mRNA expression compared to control and LPS. We observed that both, exogenous and endogenous uterine LIF, participate in progesterone effects preventing NO increase. RU-486 and dexamethasone incubations show that progesterone anti-inflammatory action is via glucocorticoid receptors. Our data support the possibility that early pregnancy may be particularly sensitive to progesterone deficiency. Consequently, the drop of systemic progesterone could be one of the mechanisms by which inflammation induced miscarriage. In this context, we propose that progesterone reduction levels have a damaging effect on the mechanism of tolerance, possibly affecting cytokine action. Therefore, the hormonal-cytokine network at the feto-maternal interface has a decisive role on successful pregnancy. Moreover, our results confirm the benefit of a preventative hormonal therapy as a good option for the treatment of risk of miscarriage.