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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
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Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.
Correspondence to Dr. Ralph Kettritz, Division of Nephrology, Franz Volhard Clinic, Wiltbergstrasse 50, 13122 Berlin, Germany. Phone: 49-30-9417-2202; Fax: 49-30-9417-2206; E-mail: kettritz{at}fvk-berlin.de
Abstract. Antineutrophil cytoplasmic antibodies (ANCA) may be
important in the pathophysiology of necrotizing vasculitis. ANCA activate
human neutrophils primed with tumor necrosis factor-
(TNF-)
in vitro. TNF- priming results in translocation of ANCA
antigens to the cell surface, where they are recognized by the antibodies. The
signaling mechanisms involved in TNF- priming and subsequent
ANCA-induced activation were investigated. TNF--primed neutrophils were
stimulated with monoclonal antibodies (MAb) to human myeloperoxidase (MPO) and
proteinase 3 (PR3), and with preparations of human ANCA (three patients with
PR3-ANCA and two patients with MPO-ANCA). Respiratory burst was measured with
superoxide dismutase-inhibitable ferricytochrome C reduction and using
dihydro-rhodamine-1,2,3. Phosphorylation of p38 mitogen-activated protein
kinase (p38-MAPK) and the extracellular signal-regulated kinase (ERK) were
assessed by immunoblotting. ANCA-antigen translocation was studied by flow
cytometry. The tyrosine phosphorylation inhibitor genistein, but not
calphostin or staurosporin, resulted in a significant dose-dependent
superoxide generation inhibition (11.6 ± 1.7 nmol to 2.1 ± 0.5
for PR3-ANCA, and 16.0 ± 2.8 to 3.3 ± 1.3 for MPO-ANCA). The
p38-MAPK inhibitor (SB202190) and the ERK inhibitor (PD98059) diminished
PR3-ANCA-mediated superoxide production dose dependently (11.6 ± 1.7
nmol O2- to 1.9 ± 0.6 with 50 µM SB202190 and
4.0 ± 0.6 with 50 µM PD098059, respectively). For MPO-ANCA, the
results were similar (16.0 ± 2.8 nmol to 0.9 ± 1.0 nmol with
SB202190 and 6.4 ± 2.4 nmol with PD98059, respectively). Western blot
showed phosphorylation of both p38-MAPK and ERK during TNF- priming.
The p38-MAPK inhibitor and the ERK inhibitor showed the strongest effect on
respiratory burst when added before TNF- priming, further supporting an
important role for both signaling pathways in the priming process. Flow
cytometry showed that p38-MAPK inhibition decreased the translocation of PR3
(by 93 ± 2%) and of MPO (by 64 ± 2%). In contrast, no such
effect was seen when ERK was inhibited. Thus, p38-MAPK and ERK are important
for the TNF--mediated priming of neutrophils enabling subsequent
ANCA-induced respiratory burst. However, both pathways show differential
effects, whereby p38-MAPK controls the translocation of ANCA antigens to the
cell surface.
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