Background: Dysregulated inflammation leads to morbidity and mortality in neonates. Neutrophil-mediated inflammation can cause inflammatory tissue damage. The mammalian target of rapamycin (mTOR) pathway governs IL-6Rα protein expression in human neutrophils. Shed IL-6Rα then participates in trans-signaling of IL-6/IL-6Rα to cells not otherwise sensitive to IL-6. Signaling to endothelial cells triggers efferocytosis where macrophages limit persistent inflammation by phagocytizing neutrophils. We hypothesized that preterm neonatal PMNs fail to synthesize IL-6Rα due to alterations in mTOR signaling.
Methods: We studied IL-6Rα expression, PAF receptor expression, and mTOR signaling in plasma and PAF-stimulated PMNs isolated from newborn infants and healthy adults using ELISA, real-time RT-PCR, western blotting, flow cytometry, and immunocytochemistry with phospho-specific antibodies.
Results: Compared to healthy adults, plasma from neonates contains significantly less soluble IL-6Rα. IL-6Rα mRNA expression in PAF-stimulated PMNs does not differ between neonates and adults, but IL-6Rα protein expression is decreased in preterm neonatal PMNs. Rapamycin, an mTOR inhibitor, blocks IL-6Rα protein expression. mTOR signaling following PAF stimulation is decreased in preterm neonatal PMNs.
Conclusions: Preterm neonatal PMNs exhibit decreased mTOR pathway signaling leading to decreased IL-6Rα synthesis. Decreased synthesis of IL-6Rα by neonatal PMNs may result in decreased IL-6/IL-6Rα trans-signaling with prolonged inflammatory response and increased morbidity.