DIFFERENTIAL SENSITIVITY TO ESCHERICHIA-COLI INFECTION IN MICE LACKING TUMOR-NECROSIS-FACTOR P55 OR INTERLEUKIN-1 P80 RECEPTORS

Objective: To determine the effect of targeted disruption of the cellu lar receptors of either tumor necrosis factor alpha (TNF-alpha) or int erleukin-1 beta (IL-1 beta) during experimental gram-negative bacteria l infection and endotoxemia. Design: Transgenic (knockout [KO]) mice d eficient in either the p55 TNF receptor (TNF RI) or the p80 IL-l recep tor (IL-1 RI) were challenged with intravenous lipopolysaccharide (end otoxin) or intraperitoneal live Escherichia coli 0111:B4. Mortality wa s assessed daily for 7 days. Serum endotoxin levels and quantitative b lood cultures were monitored at multiple times during infection. Setti ng: Surgical infectious disease research laboratory. Main Outcome Meas ures: Mortality, results of quantitative blood cultures, and serum end otoxin levels. Results: Both TNF and IL-1 RI KO mice were resistant to endotoxin challenge (0% mortality for both groups) compared with cont rol mice (100% mortality [P<.01]). In contrast, only the IL-l RI KO mi ce 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 co ntrol 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 cellula r activation by each respective cytokine. Absence confers protection a gainst intravenous endotoxin, which stimulates massive rapid release o f cytokines into the systemic circulation. However, bacterial infectio n within the peritoneal cavity is known to cause more delayed cytokine release, and cytokines may act at the site of infection to enhance ho st defenses. We believe that IL-1 signaling may be more critical in pr ovoking lethal systemic toxic effects than TNF signaling. However, TNF signaling may be an important component of host defense enhancement a t the local site of infection.