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
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
SN - 1523-1755
VL - 69
SP - 605
EP - 615
JO - Kidney International
JF - Kidney International
IS - 3
ER -