title: Interleukin-18 stimulates a positive feedback loop during renal obstruction via interleukin-18 receptor.
abstract: OBJECTIVE
  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.
  
  
  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.affiliation: Department of Urology, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana 46202, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: VanderBrink
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Karen
authors.initials: K
authors.lastname: Hile
authors.forename: Honji
authors.initials: H
authors.lastname: Zhang
authors.forename: Richard C
authors.initials: RC
authors.lastname: Rink
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007668:Kidney / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism*
chemical_list: D020382:Interleukin-18; D012333:RNA, Messenger; D053724:Receptors, Interleukin-18