The role of anti-tumor necrosis factor-alpha and interleukin-10 in protecting murine neonates from Escherichia coli sepsis

Background/Purpose: The neonate is at much higher risk for septic complicat ions and death than the adult. Although some aspects of the infant's immune response are immature, others are fully functional. Many models of septic death are caused by an overexpression of proinflammatory cytokines. If ther e were inadequate down regulatory mechanisms, this could lead to an over ex pression of proinflammatory cytokines. The authors hypothesized that the hi gh mortality rate of the newborn was caused by overexpression of tumor necr osis factor (TNF-alpha) and that interleukin-10 (IL-10) would attenuate thi s response. The aim of this study was to determine if TNF-alpha plays an im portant role in early death from Escherichia coli sepsis in the newborn ani mal and if blocking TNF improves survival. Methods: A dose response curve was determined for 1 day old C3H/HEN mice us ing 10(5) intraperitoneal E coli resulting in a 30% to 50% mortality rate. Litters of newborn (1 day old) C3H/HEN mice received a subcutaneous injecti on of either 25 or 50 ng of murine IL-10 or 20 mu L of anti-TNF-alpha 4 hou rs before a bacterial challenge. Control animals received nothing. Animals were observed for 5 to 7 days. At least 6 litters (18 pups per group) were used for each regimen. Results: Anti-TNF-alpha resulted in a significant improvement in survival r ate compared with controls (100% v 53%, P < .001). In separate experiments, IL-10 at a dose of 25 ng failed to produce any improvement in survival; ho wever, a 50-ng dose resulted in a significant improvement in treated animal s compared with controls (95% v 65%, P < .01). Conclusions: TNF-alpha plays an important role in neonatal sepsis, suggesti ng that the newborn mouse is capable of mounting a significant proinflammat ory response to Gramnegative bacteria. Newborn mice may respond to bacteria l challenge with an overexpression of proinflammatory cytokines or an under production of downregulating cytokines. Future attempts at immunomodulation in human infants must be undertaken with caution until the inflammatory re sponse is better defined. Copyright (C) 2000 by W.B. Saunders Company.