Interleukin 1 and Its Relationship to Endotoxin Tolerance

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 μg/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.