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(Journal of Leukocyte Biology. 2002;71:996-1004.)
© 2002 by Society for Leukocyte Biology

Wegener’s granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release—role of autocrine cell activation

Katja Hattar^*, Annette Bickenbach^*, Elena Csernok, Simone Rosseau^*, Ulrich Grandel^*, Werner Seeger^*, Friedrich Grimminger^* and Ulf Sibelius^*

^* Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany; and
Department of Rheumatology, Medical University of Lübeck, Germany

Correspondence: Dr. Ulf Sibelius, Department of Internal Medicine, Justus-Liebig-University Giessen, D-35385 Giessen, Germany. E-mail: ulf.sibelius{at}innere.med.uni-giessen.de

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 (TNF-) and interleukin (IL)-1ß and delayed release of IL-6, IL-8, and thromboxane A₂ (TxA₂). 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 (FcR) was apparently mandatory for monocyte activation. Using soluble receptors for TNF- and IL-1ß and a Tx receptor antagonist, we noted that the "early" cytokines functioned as inducers of TxA₂, 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-, IL-1ß, and TxA₂ function as facilitators of the secretory response. These mechanisms may contribute to inflammatory tissue injury in WG.

Key Words: autoimmunity • macrophages • lipid mediators • inflammation

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