IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis

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In antineutrophil cytoplasm autoantibody (ANCA)- associated systemic vasculitis (ASV), autoantibody-induced neutrophil activation is believed to cause organ damage. In vitro, tumor necrosis factor alpha (TNF alpha) primes neutrophils for ANCA stimulation and TNF alpha blockade has been successfully used to treat ASV. Nonetheless, irreversible organ damage can still occur, suggesting that other cytokines may circumvent TNF alpha blockade. We report that interleukin (IL)-18 deposition, as assessed by immunoperoxidase staining, is increased in renal biopsies from ASV patients. Immunofluorescence microscopy demonstrated that podocytes are the predominant glomerular IL-18-positive cell type, whereas in the interstitium, myofibroblasts, distal tubular epithelium, and infiltrating macrophages stained for IL-18. In vitro, IL-18 primed superoxide production by ANCA-activated neutrophils comparably to TNF alpha. IL-18-primed, ANCA-induced superoxide production was unaffected by anti-TNF alpha antibody, which abrogated TNF alpha priming. Furthermore, TNF alpha and IL-18 phosphorylated neutrophil p38 mitogen-activated protein kinase (MAPK), but IL-18-mediated p38 MAPK phosphorylation was unaffected by anti-TNF alpha antibody. The p38 MAPK inhibitor, SB20358, reduced IL-18-primed, ANCA-induced superoxide production in a concentration-dependent manner. ANCA-induced superoxide release was also sensitive to the Leukotriene B4 (LTB4) inhibitor MK-886. IL-18 priming was not associated with increased ANCA antigen expression on isolated neutrophils. We conclude that IL-18 is likely to be important for neutrophil recruitment and priming in ASV. Therapies targeting single priming agents may have limited efficacy in controlling disease.


Original languageEnglish
Pages (from-to)605-615
Number of pages11
JournalKidney International
Issue number3
Publication statusPublished - 1 Feb 2006


  • TNF alpha, IL-18, vasculitis, ANCA, neutrophils