AUTHOR=Presicce Pietro , Roland Cynthia , Senthamaraikannan Paranthaman , Cappelletti Monica , Hammons McKensie , Miller Lisa A. , Jobe Alan H. , Chougnet Claire A. , DeFranco Emily , Kallapur Suhas G. 

TITLE=IL-1 and TNF mediates IL-6 signaling at the maternal-fetal interface during intrauterine inflammation

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1416162

DOI=10.3389/fimmu.2024.1416162

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p>IL6 signaling plays an important role in triggering labor and IL6 is an established biomarker of intrauterine infection/inflammation (IUI) driven preterm labor (PTL). The biology of IL6 during IUI at the maternal-fetal interface was investigated in samples from human subjects and non-human primates (NHP).</p></sec><sec><title>Methods</title><p>Pregnant women with histologic chorioamnionitis diagnosed by placenta histology were recruited (n=28 term, n=43 for preterm pregnancies from 26-36 completed weeks of gestation). IUI was induced in Rhesus macaque by intraamniotic injection of lipopolysachharide (LPS, n=23). IL1 signaling was blocked using Anakinra (human IL-1 receptor antagonist, n=13), and Tumor necrosis factor (TNF) signaling was blocked by anti TNF-antibody (Adalimumab n=14). The blockers were given before LPS. All animals including controls (intraamniotic injection of saline n=27), were delivered 16h after LPS/saline exposure at about 80% gestation.</p></sec><sec><title>Results</title><p>IUI induced a robust expression of <italic>IL6</italic> mRNAs in the fetal membranes (chorion-amnion-decidua tissue) both in humans (term and preterm) and NHP.  The major sources of <italic>IL6</italic> mRNA expression were the amnion mesenchymal cells (AMC) and decidua stroma cells. Additionally, during IUI in the NHP, <italic>ADAM17</italic> (a protease that cleaves membrane bound IL6 receptor (IL6R) to release a soluble form) and <italic>IL6R</italic> mRNA increased in the fetal membranes, and the ratio of IL6 and soluble forms of IL6R, gp130 increased in the amniotic fluid signifying upregulation of IL6 trans-signaling. Both IL1 and TNF blockade suppressed LPS-induced <italic>IL6</italic> mRNAs in the AMC and variably decreased elements of IL6 trans-signaling.</p></sec><sec><title>Discussion</title><p>These data suggest that IL1 and TNF blockers may be useful anti-inflammatory agents via suppression of IL6 signaling at the maternal-fetal interface.</p></sec>