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

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@article{7110407f33d24e18be8c4bc70af6ff27,
title = "IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis",
abstract = "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.",
keywords = "TNF alpha, IL-18, vasculitis, ANCA, neutrophils",
author = "Peter Hewins and Matthew Morgan and Neil Holden and Desley Neil and Julie Williams and Caroline Savage and Lorraine Harper",
year = "2006",
month = feb,
day = "1",
doi = "10.1038/sj.ki.5000167",
language = "English",
volume = "69",
pages = "605--615",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "3",

}

RIS

TY - JOUR

T1 - IL-18 is upregulated in the kidney and primes neutrophil responsiveness in ANCA-associated vasculitis

AU - Hewins, Peter

AU - Morgan, Matthew

AU - Holden, Neil

AU - Neil, Desley

AU - Williams, Julie

AU - Savage, Caroline

AU - Harper, Lorraine

PY - 2006/2/1

Y1 - 2006/2/1

N2 - 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.

AB - 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.

KW - TNF alpha

KW - IL-18

KW - vasculitis

KW - ANCA

KW - neutrophils

U2 - 10.1038/sj.ki.5000167

DO - 10.1038/sj.ki.5000167

M3 - Article

C2 - 16514436

VL - 69

SP - 605

EP - 615

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 3

ER -