The cytokine TWEAK modulates renal tubulointerstitial inflammation.
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-kappaB in a murine tubular epithelial cell line (MCT). NF-kappaB activation was associated with degradation of IkappaB-alpha; 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-kappaB activation, chemokine and IL-6 expression, and interstitial inflammation in mice. Parthenolide, which prevents IkappaB-alpha degradation, inhibited TWEAK-induced NF-kappaB 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-kappaB-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.
Sanz
Ana Belen
AB
Unidad de Diálisis, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain.
Justo
Pilar
P
Sanchez-Niño
Maria Dolores
MD
Blanco-Colio
Luis Miguel
LM
Winkles
Jeffrey A
JA
Kreztler
Matthias
M
Jakubowski
Aniela
A
Blanco
Julia
J
Egido
Jesús
J
Ruiz-Ortega
Marta
M
Ortiz
Alberto
A
D000818:Animals; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D006801:Humans; D051379:Mice; D009395:Nephritis, Interstitial / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000494:pharmacology / Q000502:physiology*
D000074049:Cytokine TWEAK; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors