Protective effect of tumor necrosis factor-α against subsequent endotoxemia in mice is mediated, in part, by interleukin-10

Objective: Tumor necrosis factor (TNF)-alpha administration in large amounts can induce a state of shock similar to that observed in patients suffering from septic shock. Small doses of TNF-alpha induce only mild, transient hemodynamic alterations and can confer protection against subsequent inflammatory stimuli, The objective of this study was to determine whether this protective mechanism could be attributed to activity of the antiinflammatory cytokine interleukin (IL)-10. Design: Prospective, randomized, controlled study. Setting. Investigative intensive care unit at a medical university. Subjects: Female BALB-c mice, 10-12 wks of age (similar to 20 g). Interventions. All mice were subjected to intraperitoneal (ip) injection of lipopolysaccharide (LPS; Escherichia coli 0111:B4,125 jig). Mice were randomly assigned to the following groups: TNF-alpha, pretreated (100 mug ip 24 hrs before LPS); control (TNF vehicle alone 24 hrs before LPS); TNF/anti-IL-10 pretreated (TNF pretreatment as above and a neutralizing anti-IL-10 antibody); TNF/antiIL-10 control (TNF pretreatment as above and an isotype-matched control antibody with no IL-10 activity); IL-10 (100 mug ip 1 hr before LPS); and IL-10 control (IL-10 vehicle 1 hr before LPS). Measurements and Main Results: Mice were observed for a 48-hr period after endotoxin administration. Mortality in each group was recorded. Separate groups of mice were pretreated with TNF (or vehicle) and killed at 0, 2, or 4 hrs after LPS injection for collection of serum and peritoneal lavage samples that were used to assay IL-10 concentrations. A small dose of TNF-alpha attenuated mortality in mice that were subsequently injected with a highly lethal dose of endotoxin and observed for 48 hrs. Peritoneal lavage fluid concentrations of IL-10 were consistently higher in TNF-pretreated mice after endotoxin administration. The TNF-alpha protective effect was reversed by administration of a neutralizing antibody directed against murine IL-10. Conclusions. These findings indicate that administration of a low dose of TNF-alpha can induce cross-tolerance to endotoxin by induction of endogenous anti-inflammatory mechanisms.