Differential effect of caspase inhibition on proinflammatory cytokine release in septic patients.

The interleukins (IL)-1beta and IL-18 represent potent players in the proinflammatory cytokine cascade. Their activation is regulated predominantly through the IL-1-converting enzyme (ICE)/caspase-1. The role of caspases in the secretion of IL-1beta and IL-18, as well as in the release of the secondary-induced cytokines IL-12 and interferon (IFN)-gamma in whole blood from septic patients compared to healthy controls, was studied. Inhibition of caspase activity by Z-VAD significantly reduced lipopolysaccharide (LPS) and Staphylococcus aureus (SAC) induced release of mature IL-1beta in septic patients and controls. In contrast, in whole blood from septic patients significantly elevated basal level of IL-18 were found, which could neither be further increased by LPS or SAC, nor be inhibited by Z-VAD. Release of IL-12 p40 was significantly lower in septic patients compared to controls and was not affected by Z-VAD. Despite high levels of IL-18, IFN-gamma was not detected in whole blood from septic patients even after stimulation with SAC or LPS. Thus, during sepsis, caspases participate in the processing of IL-1beta, whereas maturation of IL-18 during sepsis appears to be independent of caspases. The lack of IFN-gamma release seen in septic patients could be attributed to low IL-12 release rather than to diminished IL-18 release.

Sepsis after severe injury interrupts caspase-dependent processing of interleukin-18.

BACKGROUND: Cysteine proteases (caspases) participate in the activation process of interleukin-18 (IL-18), a key cytokine for septic organ failure. This study evaluates the influence of caspase blockade on secretion of IL-18 into whole blood in patients with multiple injuries and in patients with severe sepsis. METHODS: Heparinized blood was collected from patients with multiple injuries, from septic patients, as well as from healthy humans. Whole blood was stimulated for 24 hours with lipopolysaccharide (LPS) or Staphylococcus aureus in the presence or absence of the caspase inhibitors Z-VAD and Z-DEVD. IL-18 was measured by enzyme-linked immunosorbent assay. RESULTS: S. aureus Cowan strain differentially increased the release of IL-18 in the three study populations, whereas LPS was ineffective. Z-VAD and to a lesser degree Z-DEVD decreased (p < 0.05) S. aureus Cowan strain I-induced secretion of IL-18 into whole blood from control subjects and trauma patients. Caspase inhibitors did not influence release of IL-18 into whole blood from septic patients. CONCLUSION: Secretion of IL-18 into whole blood from healthy humans and trauma patients can be effectively controlled through blockade of caspase activity. In contrast, during sepsis, alternative mechanisms may regulate secretion of IL-18.