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

被引:356
|
作者
Melnikov, VY
Ecder, T
Fantuzzi, G
Siegmund, B
Lucia, MS
Dinarello, CA
Schrier, RW
Edelstein, CL
机构
[1] Univ Colorado, Sch Med, Dept Med, Div Renal Dis & Hypertens, Denver, CO 80262 USA
[2] Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA
来源
JOURNAL OF CLINICAL INVESTIGATION | 2001年 / 107卷 / 09期
关键词
D O I
10.1172/JCI12089
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1145 / 1152
页数:8
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