IL-18 translational inhibition restricts IFN-gamma expression in crescentic glomerulonephritis

Kidney Int. 2003 Jul;64(1):160-9. doi: 10.1046/j.1523-1755.2003.00077.x.


Background: Interleukin-18 (IL-18), a potent inducer of interferon gamma (IFN-gamma) production, is a cytokine involved in the cell-mediated immune response that is expressed during inflammatory and pathologic conditions. IFN-gamma plays a role in the development of some models of glomerulonephritis (GN); however, the role of IL-18 in the production of IFN-gamma during these pathologies has not been studied.

Methods: Rat IL-18 cDNA was isolated and the regulation of IL-18 gene expression was studied. IFN-gamma and IL-18 expression were determined in anti-glomerular basement membrane (GBM) antibody (Ab)-induced GN. Recombinant active IL-18 (rIL-18) was used to further identify its effect on IFN-gamma production during this GN. Glomerular injury and levels of IFN-gamma were assayed in Wistar Kyoto (WKY) rats with anti-GBM GN in the presence or absence of rIL-18.

Results: Rat IL-18, similar to the mouse clone, requires processing by the IL-1beta converting enzyme to become activated. A rat IL-18 5'-untranslated region (UTR) translational inhibitor was identified that strongly inhibited the synthesis of IL-18. This translational inhibitor with different lengths (180 and 130 bp) was highly expressed during GN and correlated with minimal IFN-gamma mRNA expression. Injection of recombinant active IL-18 in WKY rats with anti-GBM GN was associated with an increase of glomerular IFN-gamma levels, proliferating cell nuclear antigen (PCNA)-ED1+ cells, and PCNA-CD8+ cells, with worsening of glomerular injury.

Conclusion: These data suggest that the translational control of IL-18 expression by its 5'-UTR limits the production of IL-18, resulting in restricted expression of mRNA and protein IFN-gamma in this model of GN. Furthermore, it was suggested that possible IL-18/IFN-gamma induction of local proliferation of macrophages and CD8+ cells might be an important mechanism for amplifying CD8+-mediated macrophage-dependent GN.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • 5' Untranslated Regions / metabolism
  • 5' Untranslated Regions / physiology
  • Amino Acid Sequence / genetics
  • Animals
  • Anti-Glomerular Basement Membrane Disease / metabolism*
  • Anti-Glomerular Basement Membrane Disease / pathology*
  • Base Sequence / genetics
  • COS Cells
  • Caspase 1 / genetics
  • Chlorocebus aethiops
  • Cloning, Molecular
  • Interferon-gamma / antagonists & inhibitors*
  • Interferon-gamma / genetics
  • Interleukin-18 / antagonists & inhibitors*
  • Interleukin-18 / genetics*
  • Interleukin-18 / pharmacology
  • Male
  • Molecular Sequence Data
  • Protein Biosynthesis*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Inbred WKY
  • Recombinant Proteins / pharmacology


  • 5' Untranslated Regions
  • Interleukin-18
  • RNA, Messenger
  • Recombinant Proteins
  • Interferon-gamma
  • Caspase 1