UBC Theses and Dissertations
Investigation of IL-1-beta response and caspase-1 activity in preterm neonates Jen, Roger
One of the body’s most vital functions lies in its ability to fight off invasions from microbes. Preterm neonates born less than 32 weeks of gestation represent the highest-risk patient group in terms of morbidity and mortality resulting from infections. However, data about the function of the immune system of preterm infants is deeply lacking. The interleukin-1-beta pro-inflammatory cytokine is a powerful pyrogen and inflammatory mediator implicated in several preterm diseases. IL-1-beta is produced as a precursor protein (pro-IL-1-beta) following the trigger of Toll-like receptors and secreted upon cleavage by Caspase-1 within the multi-protein NALP3 inflammasome complex. We sought to investigate early life developmental regulation mechanisms by which the production and secretion of IL-1-beta is limited before term of gestation. Our data show that preterm neonatal cord blood (CD14+) monocytes are substantially impaired in their ability to secrete IL-1-beta upon stimulation of Toll-like receptors using lipopolysaccharide. Using flow cytometry, we confirmed sufficient accumulation of the intracellular pro-IL-1-beta precursor protein in preterm cord blood monocytes. However, caspase-1 activity was markedly decreased in infants born before 29 weeks of gestation and was undetectable in some preterms born at the beginning of the second trimester (~24+ weeks), leading to an impaired cleavage and secretion of pro-IL-1-beta. Our data reveal a major mechanism responsible for the attenuation of inflammation before the term of gestation. This developmentally-regulated inhibition of Caspase-1 activity may be an important mechanism to prevent potentially harmful excessive inflammatory responses in early life.
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