Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure

J Clin Invest. 2001 May;107(9):1145-52. doi: 10.1172/JCI12089.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Kidney Injury / enzymology
  • Acute Kidney Injury / etiology*
  • Animals
  • Apoptosis
  • Caspase 1 / deficiency*
  • Caspase 1 / genetics
  • Cell Movement
  • Interleukin-18 / immunology
  • Interleukin-18 / metabolism*
  • Ischemia / enzymology
  • Ischemia / etiology*
  • Kidney Tubules / cytology
  • Mice
  • Mice, Mutant Strains
  • Neutralization Tests
  • Neutrophils
  • Peroxidase / analysis
  • Protein Processing, Post-Translational*


  • Interleukin-18
  • Peroxidase
  • Caspase 1