Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure.
We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1(-/-) mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1(-/-) ARF mice or sham-operated controls. We then injected wild-type mice with IL-18-neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1(-/-) mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1(-/-) or IL-18 antiserum-treated mice. Finally, we confirmed histologically that caspase-1(-/-) mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.
Melnikov
V Y
VY
Department of Medicine, University of Colorado School of Medicine, Denver, Colorado 80262, USA.
Ecder
T
T
Fantuzzi
G
G
Siegmund
B
B
Lucia
M S
MS
Dinarello
C A
CA
Schrier
R W
RW
Edelstein
C L
CL
D058186:Acute Kidney Injury / Q000201:enzymology / Q000209:etiology*; D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics; D002465:Cell Movement; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism*; D007511:Ischemia / Q000201:enzymology / Q000209:etiology*; D007684:Kidney Tubules / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D009500:Neutralization Tests; D009504:Neutrophils; D009195:Peroxidase / Q000032:analysis; D011499:Protein Processing, Post-Translational
D020382:Interleukin-18; D009195:Peroxidase; D020170:Caspase 1