l-663536 and Glomerulonephritis

Topics: Animals; Asthma; Glomerulonephritis; Humans; Hydroxyurea; Indoles; Inflammatory Bowel Diseases; Leukotriene Antagonists; Leukotrienes; Membrane Proteins; Propionates; Psoriasis; Quinolines; Receptors, Leukotriene

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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autoimmune Diseases; Blotting, Western; Female; Glomerulonephritis; Humans; Imidazoles; Immunohistochemistry; Indoles; Interleukin-18; Kidney; Macrophages; Male; Middle Aged; Neutrophil Activation; Neutrophils; p38 Mitogen-Activated Protein Kinases; Podocytes; Pyridines; Superoxides; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation

The modulatory effect of arachidonate 5-lipoxygenation on glomerular cell growth was assessed in rat nephrotoxic serum nephritis (NSN). After a single intravenous injection of anti-glomerular basement membrane immune serum, significant increments in glomerular proliferative activity (GPA)--assessed by tritiated thymidine incorporation in short-term glomerular cultures--occurred and were associated with enhanced glomerular cell proliferation, assessed in cortical sections by staining for the presence of proliferating cell nuclear antigen (PCNA) positive cells in glomeruli. Leukocyte depletion induced by x irradiation ameliorated the enhanced GPA and reduced PCNA (+) cell counts. The same effect was observed after treatment of rats with the arachidonate 5-lipoxygenase inhibitor MK886. These observations indicate that in NSN, leukocytes infiltrating glomeruli, and leukocyte-derived arachidonate 5-lipoxygenation eicosanoids promote glomerular cell proliferation.

Topics: Animals; Arachidonate 5-Lipoxygenase; Basement Membrane; Cell Count; Cell Division; Glomerular Mesangium; Glomerulonephritis; Immune Sera; Indoles; Kidney Glomerulus; Leukocyte Count; Leukotriene B4; Lipoxygenase Inhibitors; Male; Microscopy, Electron; Rats; Rats, Sprague-Dawley; X-Rays