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.
Oberholzer
A
A
Division of Trauma Surgery, University Hospital Zurich, Switzerland.
Härter
L
L
Feilner
A
A
Steckholzer
U
U
Trentz
O
O
Ertel
W
W
D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016022:Case-Control Studies; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000097:blood* / Q000187:drug effects; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000097:blood / Q000187:drug effects; D007375:Interleukin-1 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology* / Q000382:microbiology; D013211:Staphylococcus aureus
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D018664:Interleukin-12; D007371:Interferon-gamma