Cytokine cooperation in renal tubular cell injury: the role of TWEAK

Kidney Int. 2006 Nov;70(10):1750-8. doi: 10.1038/ Epub 2006 Sep 27.


Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) is a member of the TNF superfamily. TWEAK activates the Fn14 receptor, and may regulate apoptosis, proliferation, and inflammation, processes that play a significant role in pathological conditions. However, there is little information on the function and regulation of this system in the kidney. Therefore, TWEAK and Fn14 expression were studied in cultured murine tubular epithelial MCT cells and in mice in vivo. The effect of TWEAK on cell death was determined. We found that TWEAK and Fn14 expression was increased in experimental acute renal failure induced by folic acid. Cultured tubular cells express both TWEAK and the Fn14 receptor. TWEAK did not induce cell death in non-stimulated tubular cells. However, in cells costimulated with TNFalpha/interferon-gamma, TWEAK induced apoptosis through the activation of the Fn14 receptor. Apoptosis was associated with activation of caspase-8, caspase-9, and caspase-3, Bid cleavage, and evidence of mitochondrial injury. There was no evidence of endoplasmic reticulum stress. A pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp prevented TWEAK-induced apoptosis, but it sensitized cells to necrosis via generation of reactive oxygen species. In conclusion, cooperation between inflammatory cytokines results in tubular cell death. TWEAK and Fn14 may play a role in renal tubular cell injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology*
  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytokine TWEAK
  • Cytokines
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology
  • Folic Acid
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Interferon-gamma / pharmacology
  • Kidney Tubules, Proximal / drug effects
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology*
  • Mice
  • Reactive Oxygen Species / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • TWEAK Receptor
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / metabolism*


  • Amino Acid Chloromethyl Ketones
  • Cysteine Proteinase Inhibitors
  • Cytokine TWEAK
  • Cytokines
  • Reactive Oxygen Species
  • Receptors, Tumor Necrosis Factor
  • TWEAK Receptor
  • Tnfrsf12a protein, mouse
  • Tnfsf12 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factors
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Interferon-gamma
  • Folic Acid
  • Caspases