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

Abstract

Background/purpose: The neonate is at much higher risk for septic complications 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 there were inadequate down regulatory mechanisms, this could lead to an overexpression of proinflammatory cytokines. The authors hypothesized that the high mortality rate of the newborn was caused by overexpression of tumor necrosis factor (TNF-alpha) and that interleukin-10 (IL-10) would attenuate this response. The aim of this study was to determine if TNF-alpha plays an important role in early death from Escherichia coli sepsis in the newborn animal and if blocking TNF improves survival.

Methods: A dose response curve was determined for 1 day old C3H/HEN mice using 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 injection of either 25 or 50 ng of murine IL-10 or 20 microL of anti-TNF-alpha 4 hours 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 rate 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; however, a 50-ng dose resulted in a significant improvement in treated animals compared with controls (95% v 65%, P < .01).

Conclusions: TNF-alpha plays an important role in neonatal sepsis, suggesting that the newborn mouse is capable of mounting a significant proinflammatory response to gram-negative bacteria. Newborn mice may respond to bacterial challenge with an overexpression of proinflammatory cytokines or an underproduction of downregulating cytokines. Future attempts at immunomodulation in human infants must be undertaken with caution until the inflammatory response is better defined.