Maternally-administered lipopolysaccharide (LPS) increases tumor necrosis factor alpha in fetal liver and fetal brain: Its suppression by low-dose LPS pretreatment

Abstract

Lipopolysaccharide (LPS) has been associated with adverse developmental outcome, including intra-uterine fetal death (IUFD), intra-uterine growth retardation (IUGR) and neurological injury. In the LPS model, tumor necrosis factor alpha (TNF-α) is the major mediator leading to IUFD, IUGR and neurological injury. In the present study, we investigated the effect of maternally-administered LPS on TNF-α in maternal serum, amniotic fluid, fetal liver and fetal brain. The timed pregnant mice were intraperitoneally (i.p.) injected with a single dose of LPS (500 μg/kg) on gestational day 17. As expected, TNF-α was obviously increased in maternal serum and amniotic fluid in response to LPS. Although maternally-administered LPS also increased the level of TNF-α protein in fetal liver and brain, no significant difference in TNF-α mRNA level in fetal liver and brain was observed among different groups, suggesting that the increased TNF-α protein in fetal liver and brain may be transferred from either the maternal circulation or amniotic fluid or placenta. When the pregnant mice were pretreated with a low-dose LPS (10 μg/kg, i.p.) at 4, 12, 24 or 48 h before LPS (500 μg/kg, i.p.), LPS-evoked TNF-α in maternal serum and amniotic fluid was significantly inhibited. Importantly, low-dose LPS pretreatment also greatly attenuated LPS-induced increases in TNF-α protein in fetal liver and fetal brain. Taken together, these results indicate that perinatal exposure to low-dose LPS induces a reduced sensitivity to subsequent LPS challenge.