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TWEAK (tumor necrosis factor-like weak inducer of apoptosis) activates CXCL16 expression during renal

María Concepción Izquierdo1, Ana B Sanz, Sergio Mezzano

  • 1IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain.

Kidney International
|January 27, 2012
PubMed

Insights

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) upregulates kidney CXCL16, a T-cell attractant. This TWEAK-induced CXCL16 may drive kidney tubulointerstitial inflammation.

Area of Science:

  • Nephrology
  • Immunology
  • Molecular Biology

Background:

  • TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a cytokine that binds to the Fn14 receptor.
  • Kidney tubulointerstitial inflammation involves T-cell infiltration and chemokine expression.
  • The role of TWEAK and CXCL16 in kidney inflammation requires further elucidation.

Purpose of the Study:

  • To investigate the role of TWEAK and its receptor Fn14 in kidney tubulointerstitial inflammation.
  • To determine if TWEAK influences the expression of the chemokine CXCL16 in the kidney.
  • To explore the functional consequences of TWEAK-induced CXCL16 upregulation in renal tubular cells.

Main Methods:

  • Analysis of mRNA expression in experimental kidney inflammation models.
  • In vivo studies using exogenous TWEAK and anti-TWEAK antibodies in mice.
  • In vitro studies using cultured renal tubular cells.
  • Examination of human kidney biopsies.

Main Results:

  • TWEAK activation correlated with increased CXCL16 mRNA and T-cell infiltration in experimental kidney inflammation.
  • TWEAK administration increased kidney CXCL16 expression and T-lymphocyte infiltration in vivo.
  • Neutralizing anti-TWEAK antibodies reduced CXCL16 expression and lymphocyte infiltration.
  • TWEAK upregulated CXCL16 in cultured renal tubular cells via an NF-κB-dependent pathway.
  • Human kidney biopsies showed an association between tubular CXCL16/Fn14 expression and inflammatory infiltrates.

Conclusions:

  • TWEAK upregulates the expression of the chemokine CXCL16 in renal tubular epithelium.
  • This TWEAK-driven CXCL16 upregulation likely contributes to T-cell recruitment and kidney tubulointerstitial inflammation.
  • Targeting the TWEAK/Fn14/CXCL16 axis may offer a therapeutic strategy for kidney inflammatory diseases.

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