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408 TOLL-LIKE RECEPTORS AND TUMOR NECROSIS FACTOR α PRODUCTION IN NEONATAL HOST DEFENSE.
  1. T. R. La Pine1,
  2. N. H. Augustine1,
  3. J. E. Caron1,
  4. T. B. Martins1,
  5. H. R. Hill1
  1. 1Departments of Pediatrics and Pathology, University of Utah, Salt Lake City, UT

Abstract

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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