Premature infants are susceptible to many conditions which are inflammatory in nature. For this patient population which is expecting the intra-uterine environment, pathways necessary for fetal life and development may not have completed the transitions necessary for extra-uterine life. In this study, responses to tumor necrosis factor alpha were compared in human fetal and adult intestinal epithelial cell lines along with pre-weaned and post-weaned mouse intestinal sections in order to identify a potential developmental difference which may explain the heightened inflammatory response of preterm infants. The nuclear factor kappaB (NF-B) pathway regulates a wide variety of genes involved in immune and inflammatory processes. We report that compared to adult intestinal epithelial cells, immature intestinal epithelial cells have increased NF-B activity associated with increased NF-B-DNA binding and transcriptional activity. This increased activity appears due to inadequate inhibition of signaling leading to NF-B activation since there is also increased phosphorylation, ubiquitination and degradation of the inhibitor of NF-B (IB) in conjunction with decreased baseline expression and delayed resynthesis of this inhibitor. Thus, we demonstrate a potential mechanism for the heightened inflammatory response of immature intestinal epithelial cells.