title: Wegener's granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release-role of autocrine cell activation.
abstract: 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 alpha (TNF-alpha) and interleukin (IL)-1beta 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 (FcgammaR) was apparently mandatory for monocyte activation. Using soluble receptors for TNF-alpha and IL-1beta 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-alpha, IL-1beta, and TxA2 function as facilitators of the secretory response. These mechanisms may contribute to inflammatory tissue injury in WG.
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hattar
authors.forename: Annette
authors.initials: A
authors.lastname: Bickenbach
authors.forename: Elena
authors.initials: E
authors.lastname: Csernok
authors.forename: Simone
authors.initials: S
authors.lastname: Rosseau
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grandel
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ulf
authors.initials: U
authors.lastname: Sibelius
mesh_terms: D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D014890:Granulomatosis with Polyangiitis / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D009000:Monocytes / Q000276:immunology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D011453:Prostaglandins / Q000502:physiology; D011480:Protease Inhibitors / Q000276:immunology*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D016207:Cytokines; D011453:Prostaglandins; D011480:Protease Inhibitors