Essential Role for IL-10 in Resistance to Lipopolysaccharide-Induced Preterm Labor in Mice

Abstract

IL-10 is highly expressed in the uterus and placenta and is implicated in controlling inflammation-induced pathologies of pregnancy. To investigate the role of IL-10 in regulating preterm labor, the response of IL-10 null mutant mice to low-dose LPS in late gestation was evaluated. When IL-10 null mutant C57BL/6 (IL-10−/−) and control (IL-10+/+) mice were administered LPS on day 17 of pregnancy, the dose of LPS required to elicit 50% preterm fetal loss was 10-fold lower in IL-10−/− mice than in IL-10+/+ mice. Surviving fetuses in IL-10−/− mice exhibited fetal growth restriction at lower doses of LPS than IL-10+/+ mice. Marked elevation of LPS-induced immunoactive TNF-α and IL-6 was evident in the serum, uterus, and placenta of IL-10−/− mice, and TNF-α and IL-6 mRNA expression was elevated in the uterus and placenta, but not the fetus. Serum IL-1α, IFN-γ, and IL-12p40 were increased and soluble TNFRII was diminished in the absence of IL-10, with these changes also reflected in the gestational tissues. Administration of rIL-10 to IL-10−/− mice attenuated proinflammatory cytokine synthesis and alleviated their increased susceptibility to preterm loss. Exogenous IL-10 also protected IL-10+/+ mice from fetal loss. These data show that IL-10 modulates resistance to inflammatory stimuli by down-regulating proinflammatory cytokines in the uterus and placenta. Abundance of endogenous IL-10 in gestational tissues is therefore identified as a critical determinant of resistance to preterm labor, and IL-10 may provide a useful therapeutic agent in this common condition.

IL-1 Receptor Antagonist Protects against Placental and Neurodevelopmental Defects Induced by Maternal Inflammation

“…Thus, data from our model do not enable a useful discussion on the effect of IL-1Ra, as compared with other molecules, on preterm delivery. In sum, our results are in agreement with those showing that various proinflammatory cytokine blockade strategies and downstream production of PG have protective gestational effects (46).…”

Nod1 Activation by Bacterial iE-DAP Induces Maternal–Fetal Inflammation and Preterm Labor

“…High LPS doses are needed to induce trophoblast inflammation and in wild type mice, preterm labor (5,46). However, lower doses of LPS can also induce inflammation and prematurity in vivo, but only when the genetic background of the animal is altered, for example in IL-10 2/2 mice (47,48). At a lower dose of 750 mg, which did not induce preterm delivery, we found iE-DAP reduced fetal weight and altered cytokine profiles.…”

The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10

“…A role for IL-10 in pregnancy is supported by the observations that IL-10 null mice (7/7) are more susceptible to lipopolysaccharide (LPS)-induced fetal loss [63], and that the administration of recombinant IL-10 to pregnant mice, rats, and rhesus monkeys challenged with LPS, Escherichia coli, or IL-1b, reduces the intra-amniotic concentrations of pro-inflammatory cytokines and prostaglandins, as well as the proportion of preterm fetal losses, preterm deliveries, and the severity of fetal white matter lesions when compared to non IL-10 treated controls [63][64][65][66]. In addition, some polymorphisms in the IL-10 gene appeared to confer susceptibility to preterm birth [67][68][69] and to neonatal inflammationassociated adverse outcome [70,71].…”