TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity

J Clin Invest. 2002 Sep;110(6):835-42. doi: 10.1172/JCI15606.


The purpose of these studies was to examine the role of cytokines in the pathogenesis of cisplatin nephrotoxicity. Injection of mice with cisplatin (20 mg/kg) led to severe renal failure. The expression of cytokines, chemokines, and ICAM-1 in kidney was measured by ribonuclease protection assays and RT-PCR. We found significant upregulation of TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, TCA3, IL-1beta, and ICAM-1 in kidneys from cisplatin-treated animals. In addition, serum, kidney, and urine levels of TNF-alpha measured by ELISA were increased by cisplatin. Inhibitors of TNF-alpha production (GM6001, pentoxifylline) and TNF-alpha Ab's reduced serum and kidney TNF-alpha protein levels and also blunted the cisplatin-induced increases in TNF-alpha, TGF-beta, RANTES, MIP-2, MCP-1, and IL-1beta, but not ICAM-1, mRNA. In addition, the TNF-alpha inhibitors also ameliorated cisplatin-induced renal dysfunction and reduced cisplatin-induced structural damage. Likewise, TNF-alpha-deficient mice were resistant to cisplatin nephrotoxicity. These results indicate cisplatin nephrotoxicity is characterized by activation of proinflammatory cytokines and chemokines. TNF-alpha appears to play a central role in the activation of this cytokine response and also in the pathogenesis of cisplatin renal injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury / chemically induced*
  • Acute Kidney Injury / metabolism*
  • Animals
  • Antineoplastic Agents / toxicity
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Cisplatin / toxicity*
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Dipeptides / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Kidney / cytology
  • Kidney / drug effects
  • Kidney / injuries
  • Kidney / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Pentoxifylline / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*


  • Antineoplastic Agents
  • Chemokines
  • Cytokines
  • Dipeptides
  • Enzyme Inhibitors
  • N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide
  • Tumor Necrosis Factor-alpha
  • Cisplatin
  • Pentoxifylline