Antenatal Suppression of IL-1
Protects against Inﬂammation-Induced Fetal Injury and Improves Neonatal and Developmental Outcomes in Mice
Preterm birth (PTB) is commonly accompanied by in utero fetal inﬂammation, and existing tocolytic drugs do not target fetal inﬂam-matory injury. Of the candidate proinﬂammatory mediators, IL-1 appears central and is sufﬁcient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the com-petitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efﬁcacy in blocking IL-1 actions. Antenatal ex-posure to IL-1b induced Tnfa, Il6, Ccl2, Pghs2,and Mpges1 expression in placenta and fetal membranes, and it elevated amniotic ﬂuid IL-1b,IL-6,IL-8,and PGF2a, resulting in PTB and marked neonatal mortality. Surviving neonates had increased Il1b, Il6, Il8, Il10, Pghs2, Tnfa,and Crp expression in WBCs, elevated plasma levels of IL-1b, IL-6, and IL-8, increased IL-1b, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no beneﬁt for gestation length, neonatal mortality, or placental inﬂammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inﬂammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic. The Journal of Immunology, 2017, 198: 2047–2062.