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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado (S.F., E.C.L., L.R., T.S.H., H.S., D.-J.O., L.L., C.L.K., C.A.D., C.L.E.); and Department of Pathology, University Hospital Dubrava, Zagreb, Croatia (D.L.)

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)-1β, IL-18, IL-6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1β, IL-18, and IL-6 and neutrophil recruitment in cisplatin-induced ARF. We first examined IL-1β; renal IL-1β 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-1β, IL-18, and IL-6 and neutrophil infiltration in the kidney. However, inhibition of IL-1β, IL-18, and IL-6 or neutrophil infiltration in the kidney is not sufficient to prevent cisplatin-induced ARF.

Address correspondence to: Dr. Charles L. Edelstein, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Box C281, 4200 E. 9th Ave, Denver, CO 80262. E-mail: charles.edelstein{at}uchsc.edu

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