267. Interleukin-10 inhibits TNFα synthesis and protects against LPS-induced miscarriage and preterm labour

Abstract

The immune-deviating and anti-inflammatory cytokine interleukin-10 (IL-10) is expressed throughout pregnancy in the decidual and placental tissues. Mice with a null mutation in the IL-10 gene mice are fertile with no reduction in litter size, although fetal growth trajectories and placental structure are altered. IL-10 is known to terminate inflammatory responses and to limit inflammation-induced tissue pathology by inhibiting macrophage synthesis of tumor necrosis factor-α (TNFα). To investigate the anti-inflammatory role of IL-10 in pregnancy, the susceptibility of null mutant mice to low dose LPS-induced miscarriage and preterm labour has been evaluated. When IL-10 null mutant C57Bl/6 (IL-10–/–) and control (IL-10+/+) mice were given low dose E.coli LPS on d10 of pregnancy, IL-10 deficiency was associated with greater fetal loss with fewer mated IL-10–/– mice carrying viable fetuses at day 18 and increased rate of fetal resorption. In mice treated with LPS on day 17, preterm delivery within 24 h occurred in a higher proportion of IL-10–/– mice than IL-10+/+ mice. LPS induced very high and sustained TNFα and IL-6 content in serum, uterine and placental tissue in IL-10–/– mice, associated with upregulated mRNA expression of both cytokines in gestational tissues. These data show that IL-10 modulates placental resistance to inflammatory stimuli by down-regulating expression of the pro-inflammatory cytokines TNFα and IL-6. We conclude that IL-10 has a dual role in pregnancy, acting to regulate placental morphogenesis and fetal growth trajectory, and to protect against inflammation-induced miscarriage and preterm labour.