Lipopolysaccharide (LPS) induces leukaemia inhibitory factor (LIF) mRNA in a model of septic pregnancy loss

AISEMBERG J; VERCELLI C; BILLI S; FRANCHI AM

Rio das Pedras, Brazil

Simposio; Satellite Symposium on Reproductive Immunology; 2007

The administration of 1 mg/g of LPS to 7 day pregnant mice produced complete embryonic resorption (100%) after 24 h but it doesn´t damage the survival of the mother for future pregnancies. Endotoxin injection resulted in enhanced signs of sepsis, including bent posture, piloerection and diarrhoea and increased proiflammatory molecules production such as nitric oxide and prostaglandins at implantation sites. Progesterone, a critical sex steroid, promote allograft tolerance inducing the expression of immunomodulatory proteins in women undergoing normal pregnancies. LIF, an example of that is a secreted cytokine with pleiotropic functions which include maternal tolerance. Aim. The purpose of this work was to characterize uterine and decidual LIF mRNA production in a model of septic pregnancy loss. Methods. Balb/c females were injected intraperitoneally with LPS (1 mg/gof body weight) or vehicle (PBS) at day 7 of pregnancy. Six hours later uterine and decidual tissues were removed to determine LIF mRNA levels by RT-PCR. Serum samples were taken to determine progesterone levels by RIA. In in vitro experiments tissues were cultured in 0.5 ml DMEM culture medium which contained 50 ng/ml progesterone and incubated in a 5% CO2 humid incubator at 37°C for 48 h. Results. Females treated with LPS showed lower levels of serum progesterone compared to control females (LPS group: 35.6 ± 0.1 ng/ml vs Control group: 39.2 ± 0.4 ng/ml; p<0.01). LIF mRNA expression in LPS-treated mice was significantly higher (p<0.01) than in control group in both tissues, uterus and decidua. In vitro progesterone co-incubation increased LIF mRNA expression in control pregnant mice (p<0.01) suggesting that P4 up-regulated LIF expression in normal conditions. But, when LIF mRNA expression was increased by LPS, P4 blocked the effect of the endotoxin treatment (p<0.001). Conclusions. We think that low levels of progesterone during inflammmation leads to the immunomodulatory disorder that concludes in embryonic resorption. This study demostrates that LIF mRNA is induced in sepsis but progesterone in vitro down-regulates LIF expression under the same conditions. Taken together, these results suggest that LIF augmentation due to LPS could participate in a protective mechanism against endotoxin.