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 (original) (raw)
Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
, Eli C. Lewis, Leonid Reznikov, Danica Ljubanovic, Thomas S. Hoke, Hilary Somerset, Dong-Jin Oh, Lawrence Lu, Christina L. Klein, Charles A. Dinarello and Charles L. Edelstein
Journal of Pharmacology and Experimental Therapeutics July 2007, 322 (1) 8-15; DOI: https://doi.org/10.1124/jpet.107.119792
Abstract
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.
Footnotes
This work was supported by National Institutes of Health Grants K08 DK65022-01 (to S.F.) and R01 DK56851 (to C.L.E.) and a grant from Chung-Ang University, Department of Internal Medicine, Seoul, Korea (to D.-J.O.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.107.119792.
ABBREVIATIONS: ARF, acute renal failure; IL, interleukin; BUN, blood urea nitrogen; IL-1Ra, IL-1 receptor antagonist; IL-18BP, IL-18-binding protein; Tg, transgenic; ELISA, enzyme-linked immunosorbent assay; ATN, acute tubular necrosis; PAS, periodic acid-Schiff; ANAb, anti-neutrophil antibody; PBS, phosphate-buffered saline; caspase-1–/–, caspase-1-deficient; AS, antiserum; ECL, electrochemiluminescence; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; WY-14,643, [4-chloro-6(2,3-xylidino)-2-pyrimidinylthio] acetic acid.
- Received January 10, 2007.
- Accepted March 29, 2007.
The American Society for Pharmacology and Experimental Therapeutics
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