Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1beta, IL-18, IL-6, and neutrophil infiltration in the kidney.
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)-1beta, IL-18, IL-6, and neutrophil recruitment. We sought to determine the role of the cytokines IL-1beta, IL-18, and IL-6 and neutrophil recruitment in cisplatin-induced ARF. We first examined IL-1beta; renal IL-1beta 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-1beta, IL-18, and IL-6 and neutrophil infiltration in the kidney. However, inhibition of IL-1beta, IL-18, and IL-6 or neutrophil infiltration in the kidney is not sufficient to prevent cisplatin-induced ARF.
Faubel
Sarah
S
Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Box C281, 4200 E. 9th Ave, Denver, CO 80262, USA.
Lewis
Eli C
EC
Reznikov
Leonid
L
Ljubanovic
Danica
D
Hoke
Thomas S
TS
Somerset
Hilary
H
Oh
Dong-Jin
DJ
Lu
Lawrence
L
Klein
Christina L
CL
Dinarello
Charles A
CA
Edelstein
Charles L
CL
D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D020170:Caspase 1 / Q000502:physiology; D002945:Cisplatin / Q000633:toxicity*; D020382:Interleukin-18 / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000502:physiology
D000970:Antineoplastic Agents; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; D020170:Caspase 1; D002945:Cisplatin