The Role of Anti-Tumor Necrosis Factor-  and Interleukin-10 in Protecting Murine Neonates From Escherichia coli Sepsis By Kevin P. Lally, Emmanuel Cruz, and Hasen Xue Houston, Texas 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 over expression of proinflammatory cyto- kines. The authors hypothesized that the high mortality rate of the newborn was caused by overexpression of tumor necrosis factor (TNF-) and that interleukin-10 (IL-10) would attenuate this response. The aim of this study was to deter- mine if TNF- plays an important role in early death from Escherichia coli sepsis in the newborn animal and if blocking TNFimproves survival. M ethods: 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 new- born (1 day old) C3H/HEN mice received a subcutaneous injection of either 25 or 50 ng of murine IL-10 or 20 μL of anti–TNF- 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- 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- 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 cyto- kines 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. J Pediatr Surg 35:852-855. Copyright  2000 by W.B. Saun- ders Company. INDEX WORDS: Sepsis, cytokine, tumor necrosis factor, neonate, interleukin-10. I NFECTION REMAINS one of the most common causes of death in the hospitalized newborn. 1 Despite a wide array of antibiotics, there are many infants in whom life-threatening infection develops. The newborn has a risk of serious infection that is manyfold higher than an adult. The underlying mechanism of this increase in infectious risk is not understood entirely. Some aspects of the newborn’s immune response have been studied in detail. Defects in polymorphonuclear (PMN) chemotaxis, immunoglobulin levels, and complement activation are well known. 2-4 Many other aspects of the immune response, however, have not been well described. A number of cytokines are elaborated during an infectious insult. One of the predominant proinflamma- tory cytokines expressed early in acute infection is tumor necrosis factor alpha (TNF-). In the adult, it is widely acknowledged that an overexpression of these pro- inflammatory cytokines such as TNF- may play an important role in early acute septic death. 5,6 Interleu- kin-10 (IL-10) is also expressed during an infectious insult. One of the main stimuli for IL-10 expression is TNF. 7 IL-10 has several functions, but an important role is the downregulation of TNF. 8 IL-10 has been proposed as a possible therapeutic agent for patients with severe infections. 9 There are several animal models of infection that show a marked increase in susceptibility to endotoxin or Gram-positive bacteria in the newborn animal. 10-12 Gram- negative bacteria, however, are a more common cause of septic complications in the surgical neonate, hence, a peritonitis model may more closely mimic the clinical problem in infants after laparotomy. We hypothesized that the newborn mouse would show a significant increase in susceptibility to Escherichia coli From the Department of Surgery, The University of Texas-Houston and the Memorial Hermann Children’s Hospital, Houston, TX. Presented at the 1999 Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, Washington, DC, October 8-11, 1999. Address reprint requests to Kevin P. Lally, MD, Division of Pediatric Surgery, 6431 Fannin St, Suite 5.258, Houston, TX 77030. Copyright  2000 by W.B. Saunders Company 0022-3468/00/3506-0009$03.00/0 doi:10.1053/js.2000.6862 852 Journal of Pediatric Surgery, Vol 35, No 6 (June), 2000: pp 852-855