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Wegener’s granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release—role of autocrine cell activation
Author(s) -
Hattar Katja,
Bickenbach Annette,
Csernok Elena,
Rosseau Simone,
Grandel Ulrich,
Seeger Werner,
Grimminger Friedrich,
Sibelius Ulf
Publication year - 2002
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.71.6.996
Subject(s) - proteinase 3 , cytokine , monocyte , tumor necrosis factor alpha , biology , immunology , receptor , interleukin , autocrine signalling , anti neutrophil cytoplasmic antibody , antibody , medicine , vasculitis , autoantibody , biochemistry , disease
Antineutrophil cytoplasmic antibodies (ANCA) targeting proteinase 3 [PR3; cytoplasmic ANCA (c‐ANCA)], a leukocyte serine protease, are highly specific for Wegener’s Granulomatosis (WG). A pathogenetic role for c‐ANCA has been proposed as a result of their ability of activating neutrophils, whereas their interaction with monocytes is less well characterized. We investigated the influence of monoclonal anti‐PR3 antibodies (anti‐PR3) and c‐ANCA from WG sera on monocyte cytokine and prostanoid release. We found that PR3 was expressed on the surface of isolated monocytes. Anti‐PR3 challenge provoked a pronounced release of cytokines with early appearance of tumor necrosis factor α (TNF‐α) and interleukin (IL)‐1β and delayed release of IL‐6, IL‐8, and thromboxane A 2 (TxA 2 ). The secretory response was reproduced by c‐ANCA but not by human and murine control IgG and anti‐CD14 antibodies. Because F(ab) 2 fragments of anti‐PR3 were ineffective, coligation of Fc gamma receptors (FcγR) was apparently mandatory for monocyte activation. Using soluble receptors for TNF‐α and IL‐1β and a Tx receptor antagonist, we noted that the “early” cytokines functioned as inducers of TxA 2 , which then activated IL‐8 release. In contrast, IL‐6 formation was an independent event. We concluded that anti‐PR3 antibodies are potent inducers of monocyte cytokine and prostanoid release, and TNF‐α, IL‐1β, and TxA 2 function as facilitators of the secretory response. These mechanisms may contribute to inflammatory tissue injury in WG.