Interleukin 1 and its relationship to endotoxin tolerance
P. Leon, H. P. Redmond, J. Shou and J. M. Daly
Department of Surgery, University of Pennsylvania, Philadelphia.
Endotoxin (lipopolysaccharide [LPS])-induced cytokine release has been
implicated in the pathogenesis of sepsis. Sublethal doses of LPS induce
tolerance to a septic insult. This study evaluated pretreatment with
interleukin 1 (IL-1) against an LPS challenge and examined its relationship
to endotoxin tolerance. C3H/HeN mice (N = 100) were injected
intraperitoneally with phosphate-buffered saline (control group), IL-1 (200
micrograms/kg), or LPS (1 mg/kg) for 3 days. On day 5, peritoneal
macrophages were harvested and assayed for antimicrobial activity
(superoxide anion production and Candida albicans phagocytosis). Serum
cytokine levels and survival after an LPS challenge on day 5 were also
assessed. Pretreatment with IL-1 or LPS significantly increased superoxide
anion production, C albicans phagocytosis, and survival compared with
pretreatment with phosphate-buffered solution. Interleukin 6 levels
significantly decreased in the IL-1 and LPS groups. Peak levels of tumor
necrosis factor significantly decreased only in the LPS group. Thus,
pretreatment with IL-1 or low doses of LPS may exert protective effects by
decreasing levels of interleukin 6 while increasing antimicrobial activity.
Mice pretreated with IL-1 were protected from endotoxin despite elevated
peak levels of tumor necrosis factor, suggesting a different mechanism for
endotoxin tolerance than for tolerance to tumor necrosis factor.
