Differential sensitivity to Escherichia coli infection in mice lacking tumor necrosis factor p55 or interleukin-1 p80 receptors
R. D. Acton, P. S. Dahlberg, M. E. Uknis, H. G. Klaerner, G. S. Fink, J. G. Norman and D. L. Dunn
Department of Surgery, University of Minnesota, Minneapolis, USA.
OBJECTIVE: To determine the effect of targeted disruption of the cellular
receptors of either tumor necrosis factor alpha (TNF-alpha) or
interleukin-1 beta (IL-1 beta) 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.
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