Activated caspase-1 is not a central mediator of inflammation in the course of ischemia-reperfusion

Background Upon transplantation donor organs subjected to prolonged ischemi a suffer from reperfusion injury. Recent observations suggest that caspase activation is involved in inducing the deleterious in flammatory reaction t hat mediates reperfusion injury. Release of cytokines like interleukin (IL) -1 and IL-18 may occur during apoptosis through activation of caspase-1/IL- 1 beta -converting enzyme. We hypothesized that caspase-l activation is a k ey event in apoptosis/ caspase-dependent inflammation during the developmen t of renal reperfusion injury. Methods. Caspase-1(-/-), caspase-1(+/+) as well as Swiss mice were subjecte d to 45 min of renal ischemia and 24 hr of reperfusion, Animals were admini stered agents capable of neutralizing the pro-inflammatory activation produ cts of caspase-1 (IL-1 receptor antagonist, anti-IL-1 receptor antibody, an d anti-IL-18 antibody). The extent of renal functional deterioration, infla mmation, and apoptosis were compared. Results. No improvement in renal function as reflected by serum ureum and c reatinine were found in caspase-1(-/-) mice as compared to wild type contro ls. Caspase-1(-/-) mice showed slightly attenuated renal inflammation as in dicated by decreased renal neutrophil influx, but failed to show changes in intrarenal tumor necrosis factor-a! production. Moreover, caspase-1(-/-) m ice clearly exhibited reperfusion-induced apoptosis as reflected by renal t erminal deoxynucleotidyltransferase histology and internucleosomal DNA clea vage, Treatment with IL- receptor antagonist, anti-IL-1 receptor antibody, or anti-IL-18 antibody minimally reduced renal functional deterioration, in flammation, and apoptosis. Conclusions. These findings suggest that activated caspase-1 and its inflam matory products are involved in, but not crucial to, the induction of infla mmation after renal ischemia-reperfusion. Hence, apart from caspase-1, othe r (combinations of) activated caspases are likely to be more prominently in volved in renal reperfusion injury.