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


CONCLUSIONS
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.
Garcia
Gabriela E
GE
Department of Immunology, The Scripps Research Institute, La Jolla, California, USA.
Xia
Yiyang
Y
Ku
George
G
Johnson
Richard J
RJ
Wilson
Curtis B
CB
Feng
Lili
L
D020121:5' Untranslated Regions / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000378:metabolism* / Q000473:pathology*; D001483:Base Sequence / Q000235:genetics; D019556:COS Cells; D020170:Caspase 1 / Q000235:genetics; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000235:genetics; D020382:Interleukin-18 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000494:pharmacology
D020121:5' Untranslated Regions; D020382:Interleukin-18; D012333:RNA, Messenger; D011994:Recombinant Proteins; D007371:Interferon-gamma; D020170:Caspase 1