The Cytokine TWEAK Modulates Renal Tubulointerstitial... : Journal of the American Society of Nephrology (original) (raw)

BASIC RESEARCH

Sanz, Ana Belen*; Justo, Pilar*; Sanchez-Nin[Combining Tilde]o, Maria Dolores*; Blanco-Colio, Luis Miguel*; Winkles, Jeffrey A.†; Kreztler, Matthias‡; Jakubowski, Aniela§; Blanco, Julia‖; Egido, Jesús*; Ruiz-Ortega, Marta*; Ortiz, Alberto*

*Fundación Jiménez Díaz, Universidad Autónoma de Madrid and Fundación Renal In[Combining Tilde]igo Alvarez de Toledo, Madrid, Spain; †Departments of Surgery and Physiology, Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland; ‡Division of Nephrology, University of Michigan, Ann Arbor, Michigan; §Department of Immunobiology, BiogenIdec, Inc., Cambridge, Massachusetts; and ‖Hospital Clinico San Carlos, Madrid, Spain

Correspondence: Dr. Alberto Ortiz, Unidad de Diálisis, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. Phone: +34-655538941; Fax: +34-915-442636; E-mail: [email protected]

Accepted October 30, 2007

Received May 17, 2007

Abstract

TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of cytokines. In addition to binding and activating the fibroblast growth factor–inducible 14 receptor, TWEAK may regulate apoptosis, proliferation, and inflammation; however, the role of this system in kidney injury is unknown. In vitro, it was found that TWEAK induced the sustained activation of NF-κB in a murine tubular epithelial cell line (MCT). NF-κB activation was associated with degradation of IκB-α; translocation of RelA to the nucleus; and increased mRNA and protein expression of monocyte chemoattractant protein-1, RANTES, and IL-6. Similarly, in vivo, the systemic administration of TWEAK induced renal NF-κB activation, chemokine and IL-6 expression, and interstitial inflammation in mice. Parthenolide, which prevents IκB-α degradation, inhibited TWEAK-induced NF-κB activation and prevented the aforementioned changes in vitro and in vivo. After folic acid–induced acute kidney injury, fibroblast growth factor–inducible 14 expression increased in mouse tubular epithelium. Neutralization of TWEAK decreased the expression of chemokines in tubular cells and reduced interstitial inflammation. In conclusion, TWEAK has NF-κB–dependent proinflammatory effects on tubular epithelial cells in vitro and in vivo. Moreover, blockade of TWEAK reduces tubular chemokine expression and macrophage infiltration, suggesting that TWEAK modulates acute kidney injury by regulating the inflammatory response.