Selective IL-1α exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep

Maria Nikiforou, Matthew W. Kemp, Rick van Gorp, M. Saito, J.P. Newnham, N.L. Reynaert, L.E. Janssen, A.H. Jobe, S.G. Kallapur, Boris Kramer, Tim Wolfs*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Chorioamnionitis, caused by intra-amniotic exposure to bacteria and their toxic components, is associated with fetal gut inflammation and mucosal injury. In a translational ovine model, we have shown that these adverse intestinal outcomes to chorioamnionitis were the combined result of local gut and pulmonary-driven systemic immune responses. Chorioamnionitis-induced gut inflammation and injury was largely prevented by inhibiting interleukin-1 (IL-1) signaling. Therefore, we investigated whether local (gut-derived) IL-1alpha signaling or systemic IL-1alpha-driven immune responses (lung or chorioamnion/skin-derived) were sufficient for intestinal inflammation and mucosal injury in the course of chorioamnionitis. Fetal surgery was performed in sheep to isolate the lung, gastrointestinal tract, and chorioamnion/skin, and IL-1alpha or saline was given into the trachea, stomach, or amniotic cavity 1 or 6 days before preterm delivery. Selective IL-1alpha exposure to the lung, gut, or chorioamnion/skin increased the CD3+ cell numbers in the fetal gut. Direct IL-1alpha exposure to the gut impaired intestinal zonula occludens protein-1 expression, induced villus atrophy, changed the expression pattern of intestinal fatty acid-binding protein along the villus, and increased the CD68, IL-1, and TNF-alpha mRNA levels in the fetal ileum. With lung or chorioamnion/skin exposure to IL-1alpha, intestinal inflammation was associated with increased numbers of blood leukocytes without induction of intestinal injury or immaturity. We concluded that local IL-1alpha signaling was required for intestinal inflammation, disturbed gut maturation, and mucosal injury in the context of chorioamnionitis.Laboratory Investigation advance online publication, 26 October 2015; doi:10.1038/labinvest.2015.127.
Original languageEnglish
Pages (from-to)69-80
Number of pages12
JournalLaboratory Investigation
Issue number1
Early online date1 Jan 2015
Publication statusPublished - Jan 2016



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