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222 Enhanced TLR4 Expression and IL-8 Release in Preterm Neonates

Sepsis related morbidity in neonates is mediated through innate inflammatory responses. The initial step in inflammation is the recognition of the invading microorganisms by immune cells which leads to their activation and the clearance of pathogens. Toll-like receptors expressed on immune cells bind to pathogens and trigger the release of pro-inflammatory cytokines. Aim: To investigate the innate immune response to Gram negative bacteria in healthy neonates and adults by evaluating the effect of in vitro LPS administration on: a) TLR4 surface expression on peripheral blood monocytes and b) IL-8 and TNF-alpha release from blood cultures. Materials and Methods: Peripheral blood from 10 preterm, 10 term neonates and 10 adults was incubated for 4 hours with or without 100ng/ml LPS. For blocking experiments, blood was pre-incubated with anti-TLR4 antibody for 30 minutes. Double staining with anti-CD14 and anti-TLR4 antibodies was performed by FACS and TLR4% expression as well as mean fluorescence intensity were estimated. IL-8 and TNFalpha release were assessed by ELISA in culture's supernatant. Results:TLR4 surface expression on monocytes before LPS stimulation was significantly higher in preterm neonates as compared to adults. Following LPS administration, TLR4 expression increased in all three groups, however the increase in adults was significantly higher to that found in preterms. TNF-alpha release was similar in all three groups. IL-8 release was significantly higher in full terms and preterm neonates as compared to adults. Blocking experiments with anti-TLR4 antibody partially decreased LPS-induced IL-8 release. Conclusions: Preterm neonates have higher baseline expression of TLR4 than adults and thus may be more susceptible to bacterial infections. Although TLR4 increase following LPS was lower in preterms as compared to adults, IL-8 release was higher. The partial inhibition of TLR4 by blocking antibody suggests that IL-8 production in newborns is also mediated through TLR4 independent pathways.