Endotoxin administration to animals and humans is an accepted experimental model of Gram-negative sepsis, and endotoxin is believed to play a major role in triggering the activation of cytokines. In septic patients, the IL-12/IL-18/IFN-gamma axis is activated and correlates with mortality. Our aim was to investigate the effects of endotoxin administration in humans on the activation of the IL-12/IL-18/IFN-gamma axis. Seven healthy volunteers received E. coli endotoxin (O:113). Hemodynamics, temperature and the course of plasma concentrations of TNF-alpha, IL-1beta, IL-12, IL-18 and IFN-gamma were determined. Endotoxin administration resulted in the expected flu-like symptoms, a temperature of 38.8 +/- 0.3(o)C (p < 0.003), a decrease in mean arterial blood pressure of 14.8 +/- 1.8 mmHg (p < 0.0002) and an increase in heart rate of 27.5 +/- 4.8 bpm (p < 0.002) compared to baseline values. TNF-alpha increased from 16.6 +/- 8.2 to 927 +/- 187 pg/mL (p < 0.003). IL-1beta increased from 8.6 +/- 0.5 to 25.3 +/- 2.0 pg/mL (p < 0.0001). IL-12 showed no significant increase (8.2 +/- 0.2 to 9.3 +/- 0.8 pg/mL, p = 0.13), and all IL-18 measurements remained below the level of detection. In contrast, IFN-gamma showed an increase from 106.6 +/- 57.1 to 152.7 +/- 57.8 (p < 0.005). These results indicate that pathways other than the IL-12/IL-18 axis may induce IFN-gamma production in human endotoxemia.