Human neonates are uniquely susceptible to severe and overwhelming infections. The mechanism of this increased susceptibility is poorly understood. Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that contributes to host defense. Toll-like receptors (TLRs) are signal-transducing receptors that initiate and regulate cytokine production during inflammation. Here we examine the expression of TNF-α in cord blood after stimulation with the ligands for TLR-1 to -7. Whole blood was obtained from healthy adults and umbilical cord blood from healthy term deliveries. TNF-α production was measured in whole blood using Luminex multianalyte technology. The following TLR ligands were used: TLR-1 and -2 (PAM3CSK4), TLRs-2 and -6 (Zymosan), TLR-3 (Poly I:C), TLR-4 (LPS), TLR-5 (flagellin), and TLR-7 (Loxoribine). Adult and cord blood produce similar amounts of TNF-α in response to TLR-1 and -2 (adult: 20 pg/mL; cord: 19 pg/mL) TLR-3 and -6 (adult: 60 pg/mL; cord: 12 pg/mL), TLR-3 (adult: 14 pg/mL; cord: 2.9 pg/mL), TLR-5 (adult: 16 pg/mL; cord: 2 pg/mL), and TLR-7 (adult: 3 pg/mL; cord: 1.1 pg/mL). The TNF-α production in response to LPS, the ligand for TLR-4, however, was significantly lower in cord blood (450 pg/mL) than adult blood (733 pg/mL) (p = .025). While the highest overall production of TNF-α by cord blood was through TLR-4, peak concentrations were significantly lower than adults. We speculate that this deficiency in TLR-4 signaling may significantly contribute to the immaturity of the neonatal immune response and their increased susceptibility to infections.
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