Interleukin-18 stimulates a positive feedback loop during renal obstruction via interleukin-18 receptor

Brian A. Vanderbrink, Hiroshi Asanuma, Karen Hile, Honji Zhang, Richard C. Rink, Kirstan K. Meldrum

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Purpose: Interleukin-18 is a proinflammatory cytokine that is an important mediator of obstruction induced renal tubulointerstitial fibrosis independent of tumor necrosis factor-α and β1 activity. We hypothesized that interleukin-18 stimulates a positive feedback loop during obstruction via interleukin-18 receptor to increase interleukin-18 gene expression and protein production. Materials and Methods: Male C57BL6 interleukin-18 receptor knockout (The Jackson Laboratory, Bar Harbor, Maine) and control wild-type mice underwent unilateral ureteral obstruction or sham operation and were sacrificed 1 week after surgery. Renal cortical tissue samples were harvested and analyzed for interleukin-18 protein by enzyme-linked immunosorbent assay, and for interleukin-18 and interleukin-18 receptor gene expression by quantitative polymerase chain reaction. The specific cellular localization of interleukin-18 and interleukin-18 receptor expression during obstruction was assessed using dual labeling immunofluorescence staining. Results: Renal interleukin-18 receptor expression increased significantly in wild-type mice in response to obstruction but remained at sham operation levels in interleukin-18 receptor knockout mice. Similarly while interleukin-18 protein and gene expression were significantly increased in wild-type mice in response to obstruction, interleukin-18 levels and gene expression were significantly decreased during obstruction in knockout mice. Obstruction induced interleukin-18 and interleukin-18 receptor production were localized predominantly to tubular epithelial cells and to a lesser extent to the renal interstitium. Conclusions: Results reveal that interleukin-18 stimulates a positive feedback loop via interleukin-18 receptor during renal obstruction to stimulate interleukin-18 production and gene expression. The predominant cellular source of interleukin-18 production during renal obstruction appears to be tubular epithelial cells rather than infiltrating macrophages.

Original languageEnglish (US)
Pages (from-to)1502-1508
Number of pages7
JournalJournal of Urology
Volume186
Issue number4
DOIs
StatePublished - Oct 1 2011

Keywords

  • epithelial cells
  • gene expression
  • interleukin-18
  • kidney
  • ureteral obstruction

ASJC Scopus subject areas

  • Urology

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    Vanderbrink, B. A., Asanuma, H., Hile, K., Zhang, H., Rink, R. C., & Meldrum, K. K. (2011). Interleukin-18 stimulates a positive feedback loop during renal obstruction via interleukin-18 receptor. Journal of Urology, 186(4), 1502-1508. https://doi.org/10.1016/j.juro.2011.05.046