IL-6/IL-6R axis plays a critical role in acute kidney injury.
The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6-deficient mice were resistant to HgCl2-induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6-deficient mice than in wild-type mice, and neutrophil depletion before HgCl2 administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury,serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of trans-signaling, protects the kidney from further injury.
Nechemia-Arbely
Yael
Y
Goldyne Savad Institute of Gene Therapy, Jerusalem, 91120, Israel.
Barkan
Daniel
D
Pizov
Galina
G
Shriki
Anat
A
Rose-John
Stefan
S
Galun
Eithan
E
Axelrod
Jonathan H
JH
D058186:Acute Kidney Injury / Q000209:etiology*; D000818:Animals; D015850:Interleukin-6 / Q000502:physiology*; D051379:Mice; D019947:Receptors, Interleukin-6 / Q000502:physiology*
C508603:IL6R protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6