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Differential Sensitivity to Escherichia coli Infection in Mice Lacking Tumor Necrosis Factor p55 or Interleukin-1 p80 Receptors

Robert D. Acton, MD; Peter S. Dahlberg, MD; Marc E. Uknis, MD; Hans G. Klaerner, MD; Gregory S. Fink, MD; James G. Norman, MD; David L. Dunn, MD, PhD
Arch Surg. 1996;131(11):1216-1221. doi:10.1001/archsurg.1996.01430230098017.
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Objective:  To determine the effect of targeted disruption of the cellular receptors of either tumor necrosis factor α (TNF-α) or interleukin-1β (IL-1β) during experimental gram-negative bacterial infection and endotoxemia.

Design:  Transgenic (knockout [KO]) mice deficient in either the p55 TNF receptor (TNF RI) or the p80 IL-1 receptor (IL-1 RI) were challenged with intravenous lipopolysaccharide (endotoxin) or intraperitoneal live Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Serum endotoxin levels and quantitative blood cultures were monitored at multiple times during infection.

Setting:  Surgical infectious disease research laboratory.

Main Outcome Measures:  Mortality, results of quantitative blood cultures, and serum endotoxin levels.

Results:  Both TNF and IL-1 RI KO mice were resistant to endotoxin challenge (0% mortality for both groups) compared with control mice (100% mortality [P<.01]). In contrast, only the IL-1 RI KO mice were resistant to infection caused by viable gram-negative bacteria (43% mortality) compared with control mice (100% mortality [P<.01]). Infection led to 100% mortality in TNF RI KO mice. The IL-1 RI KO mice exhibited less bacteremia and diminished endotoxemia compared with control and TNF RI KO mice 18 and 24 hours after infection.

Conclusion:  The absence of either the TNF or the IL-1 RI receptor prevents cellular activation by each respective cytokine. Absence confers protection against intravenous endotoxin, which stimulates massive rapid release of cytokines into the systemic circulation. However, bacterial infection within the peritoneal cavity is known to cause more delayed cytokine release, and cytokines may act at the site of infection to enhance host defenses. We believe that IL-1 signaling may be more critical in provoking lethal systemic toxic effects than TNF signaling. However, TNF signaling may be an important component of host defense enhancement at the local site of infection.Arch Surg. 1996;131:1216-1221


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