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 (TNFalpha) primes neutrophils for ANCA stimulation and TNFalpha blockade has been successfully used to treat ASV. Nonetheless, irreversible organ damage can still occur, suggesting that other cytokines may circumvent TNFalpha 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 TNFalpha. IL-18-primed, ANCA-induced superoxide production was unaffected by anti-TNFalpha antibody, which abrogated TNFalpha priming. Furthermore, TNFalpha and IL-18 phosphorylated neutrophil p38 mitogen-activated protein kinase (MAPK), but IL-18-mediated p38 MAPK phosphorylation was unaffected by anti-TNFalpha 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.
authors.affiliation: Renal Immunobiology, Medical School, University of Birmingham, Birmingham, UK.
authors.forename: P
authors.initials: P
authors.lastname: Hewins
authors.forename: M D
authors.initials: MD
authors.lastname: Morgan
authors.forename: N
authors.initials: N
authors.lastname: Holden
authors.forename: D
authors.initials: D
authors.lastname: Neil
authors.forename: J M
authors.initials: JM
authors.lastname: Williams
authors.forename: C O S
authors.initials: CO
authors.lastname: Savage
authors.forename: L
authors.initials: L
authors.lastname: Harper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology* / Q000502:physiology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D015153:Blotting, Western; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D020382:Interleukin-18 / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D007668:Kidney / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D050199:Podocytes / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D007093:Imidazoles; D007211:Indoles; D020382:Interleukin-18; D011725:Pyridines; D013481:Superoxides; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C060893:MK-886; D002722:Chlorobenzenes; C093642:SB 203580