Activated caspase-1 is not a central mediator of inflammation in the course of ischemia-reperfusion.
BACKGROUND
Upon transplantation, donor organs subjected to prolonged ischemia suffer from reperfusion injury. Recent observations suggest that caspase activation is involved in inducing the deleterious inflammatory reaction that mediates reperfusion injury. Release of cytokines like interleukin (IL)-1 and IL-18 may occur during apoptosis through activation of caspase-1/IL-1beta-converting enzyme. We hypothesized that caspase-1 activation is a key event in apoptosis/ caspase-dependent inflammation during the development of renal reperfusion injury.


METHODS
Caspase-1-/-, caspase-1+/+ as well as Swiss mice were subjected to 45 min of renal ischemia and 24 hr of reperfusion. Animals were administered agents capable of neutralizing the pro-inflammatory activation products of caspase-1 (IL-1 receptor antagonist, anti-IL-1 receptor antibody, and anti-IL-18 antibody). The extent of renal functional deterioration, inflammation, and apoptosis were compared.


RESULTS
No improvement in renal function as reflected by serum ureum and creatinine were found in caspase-1-/- mice as compared to wild type controls. Caspase-1-/- mice showed slightly attenuated renal inflammation as indicated by decreased renal neutrophil influx, but failed to show changes in intrarenal tumor necrosis factor-alpha production. Moreover, caspase-1-/- mice clearly exhibited reperfusion-induced apoptosis as reflected by renal terminal deoxynucleotidyltransferase histology and internucleosomal DNA cleavage. Treatment with IL-1 receptor antagonist, anti-IL-1 receptor antibody, or anti-IL-18 antibody minimally reduced renal functional deterioration, inflammation, and apoptosis.


CONCLUSIONS
These findings suggest that activated caspase-1 and its inflammatory products are involved in, but not crucial to, the induction of inflammation after renal ischemia-reperfusion. Hence, apart from caspase-1, other (combinations of) activated caspases are likely to be more prominently involved in renal reperfusion injury.
Daemen
M A
MA
Department of General Surgery, University of Maastricht, The Netherlands.
Denecker
G
G
van't Veer
C
C
Wolfs
T G
TG
Vandenabeele
P
P
Buurman
W A
WA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D018836:Inflammation Mediators / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000201:enzymology* / Q000209:etiology / Q000517:prevention & control
D018836:Inflammation Mediators; D007375:Interleukin-1; D020382:Interleukin-18; D020170:Caspase 1