Developmentally regulated tumor necrosis factor-alpha induced nuclear factor-kappaB activation in intestinal...

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