title: Antibodies to proteinase 3 prime human oral, lung, and kidney epithelial cells to secrete proinflammatory cytokines upon stimulation with agonists to various Toll-like receptors, NOD1, and NOD2.
abstract: Antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies, the detection of which in serum can be used in the diagnosis of Wegener's granulomatosis (WG). Proteinase 3 (PR3) is a major target antigen of ANCA in WG patients, and the interaction of PR3 ANCA with leukocytes causes a debilitating autoimmune disease. The first signs and symptoms in WG patients are observed in the oral cavity, lungs, and kidneys. Human epithelial cells generally do not secrete proinflammatory cytokines upon stimulation with pathogen-associated molecular patterns (PAMPs). In this study, anti-PR3 antibodies (Abs) and PR3 ANCA-containing sera from WG patients endowed human oral, lung, and kidney epithelial cells with responsiveness to PAMPs in terms of the production of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein-1, and tumor necrosis factor alpha. Protease-activated receptor-2 (PAR-2) agonist peptides mimicked the priming effects of PR3 ANCA against PAMPs. Furthermore, the anti-PR3 Ab-mediated cell activation was significantly abolished by RNA interference targeting PAR-2 and NF-kappaB. This is the first report of priming effects of anti-PR3 Abs (PR3 ANCA) on epithelial cells. The results suggest that anti-PR3 Abs (PR3 ANCA) prime human epithelial cells to produce cytokines upon stimulation with various PAMPs, and these mechanisms may be involved in severe chronic inflammation in WG.
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan. kyoro@mail.tains.tohoku.ac.jp
authors.forename: Akiko
authors.initials: A
authors.lastname: Uehara
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Takada
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007369:Interferon Inducers / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009055:Mouth / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053146:Myeloblastin / Q000276:immunology* / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000819:agonists* / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000819:agonists* / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D019268:Antibodies, Antineutrophil Cytoplasmic; D016207:Cytokines; D018836:Inflammation Mediators; D007369:Interferon Inducers; C119067:NOD1 protein, human; C429018:NOD2 protein, human; D053474:Nod1 Signaling Adaptor Protein; D053473:Nod2 Signaling Adaptor Protein; D044464:Receptor, PAR-2; D051193:Toll-Like Receptors; D053146:Myeloblastin