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

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.

• Authors: Brian A VanderBrink, Hiroshi Asanuma, Karen Hile, Honji Zhang, Richard C Rink, Kirstan K Meldrum
• Journal: The Journal of urology (J Urol) Vol. 186 Issue 4 Pg. 1502-8 (Oct 2011) ISSN: 1527-3792 [Electronic] United States
• PMID: 21855933 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-18
• RNA, Messenger
• Receptors, Interleukin-18

Topics

• Animals
• Enzyme-Linked Immunosorbent Assay
• Feedback, Physiological
• Fluorescent Antibody Technique
• Gene Expression
• Interleukin-18 (genetics, metabolism, physiology)
• Kidney (metabolism)
• Kidney Cortex (metabolism)
• Kidney Tubules (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Polymerase Chain Reaction
• RNA, Messenger (metabolism)
• Receptors, Interleukin-18 (metabolism)
• Ureteral Obstruction (genetics, metabolism)