The Role Of Toll-Like Receptor Signaling In Preterm And Term Neonates In Infection Control

Objective:The neonates highly susceptible to infections by bacteria,fungi,and viruses and,as a result,infection remains the single most common killer in early life.Toll like receptors(TLRs) and their downstream signaling network are essential players in an evolutionary conserved first line of host defense against foreign microorganisms.We, therefore,examined the surface expression of TLRs in monocytes from term and preterm newborns.We further investigated activation of protein kinase p38 in CD14 monocytes after stimulation with LPS.The functional outcome of stimulation was determined by cytokine secretion between term and preterm neonates.Methods:Monocyte from 20 preterm newborns(＜37 weeks of gestation),50 term newborns(37-42 weeks of gestation) and 15 adults were investigated.The percentage of TLR2,TLR4 positive cells were evaluated by analysis with flow cytometry.After stimulation with LPS(10 ng/ml),the activation of protein kinases p38 was analyzed by flow cytometry among term,preterm newborns and adults.Fifty microliters of cord blood was diluted in 450μl of RPMI 1640 containing 10 ng/ml LPS.After 4 h of stimulation, cells were centrifuged.Cell-free supematants were collected.TNF-α,IL-8 and IL-6 cytokines production were analyzed by bead-based assays(CBA) between term and preterm newborns.Result:1.Rduced expression of TLR2,TLR4 reached a significance level of P＜0.001 for newborns,compared with adults.2.Stimulation of human blood ex vivo with 10 ng/ml LPS,resulted in significant differences in p38 kinase activity between the different age groups(P＜0.05).3.The levels of production of TNF-α,IL-8 and IL-6 cytokines were striking lower in monocytes from preterm newborns on stimulation with LPS than the levels in monocytes from term newborns(P＜0.05). Conclusion:The impaired Toll-like receptor signaling and the reduced functional response to bacterial cell wall components appears to be part of the functional immaturity of the neonatal immune system and might predispose newborns to bacterial infection.