Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1β, IL-18, IL-6, and neutrophil infiltration in the kidney

被引:333
作者
Faubel, Sarah
Lewis, Eli C.
Reznikov, Leonid
Ljubanovic, Danica
Hoke, Thomas S.
Somerset, Hilary
Oh, Dong-Jin
Lu, Lawrence
Klein, Christina L.
Dinarello, Charles A.
Edelstein, Charles L.
机构
[1] Univ Colorado, Sch Med, Div Renal Dis & Hypertens, Dept Med,Hlth Sci Ctr, Denver, CO 80262 USA
[2] Univ Zagreb, Dept Pathol, Hosp Dubrava, Zagreb 41000, Croatia
关键词
D O I
10.1124/jpet.107.119792
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
We have demonstrated that caspase- 1- deficient ( caspase-1(-/-)) mice are functionally and histologically protected against cisplatin- induced acute renal failure ( ARF). Caspase-1 exerts proinflammatory effects via the cytokines interleukin ( IL)-1 beta, IL-18, IL- 6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1 beta, IL-18, and IL-6 and neutrophil recruitment in cisplatin- induced ARF. We first examined IL-1 beta; renal IL-1 beta increased nearly 2- fold in cisplatin- induced ARF and was reduced in the caspase-1(-/-) mice. However, inhibition with IL- 1 receptor antagonist ( IL-1Ra) did not attenuate cisplatin- induced ARF. Renal IL- 18 increased 2.5- fold; however, methods to inhibit IL- 18 using IL- 18 antiserum and transgenic mice that overproduce IL- 18- binding protein ( a natural inhibitor of IL- 18) did not protect. Renal IL- 6 increased 3- fold; however, IL-6-deficient ( IL- 6(-/-)) mice still developed cisplatin-induced ARF. We next examined neutrophils; blood neutrophils increased dramatically after cisplatin injection; however, prevention of peripheral neutrophilia and renal neutrophil infiltration with the neutrophil- depleting antibody RB6-8C5 did not protect against cisplatin- induced ARF. In summary, our data demonstrated that cisplatin- induced ARF is associated with increases in the cytokines IL-1 beta, IL-18, and IL- 6 and neutrophil infiltration in the kidney. However, inhibition of IL-1 beta, IL-18, and IL- 6 or neutrophil infiltration in the kidney is not sufficient to prevent cisplatin- induced ARF.
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页码:8 / 15
页数:8
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