{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:02:53Z","timestamp":1761843773612},"reference-count":33,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2008,7,1]],"date-time":"2008-07-01T00:00:00Z","timestamp":1214870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Clin Vaccine Immunol"],"published-print":{"date-parts":[[2008,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>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-\u03baB. 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.<\/jats:p>","DOI":"10.1128\/cvi.00137-08","type":"journal-article","created":{"date-parts":[[2008,5,22]],"date-time":"2008-05-22T01:22:20Z","timestamp":1211419340000},"page":"1060-1066","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"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"],"prefix":"10.1128","volume":"15","author":[{"given":"Akiko","family":"Uehara","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"},{"name":"Department of Hematology and Rheumatology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiko","family":"Hirabayashi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"},{"name":"Department of Hematology and Rheumatology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruhiko","family":"Takada","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"},{"name":"Department of Hematology and Rheumatology, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/35021228","volume":"406","year":"2000","unstructured":"Aderem, A., and R. J. Ulevitch. 2000. Toll-like receptors in the induction of the innate immune response. Nature406:782-787.","journal-title":"Nature"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.015"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S1521-6616(02)00026-8","volume":"106","year":"2003","unstructured":"Bart\u016fn\u0306kov\u00e1, J., V. Tesa\u0159, and A. \u0160ediv\u00e1. 2003. Diagnostic and pathogenetic role of antineutrophil cytoplasmic autoantibodies. Clin. Immunol.106:73-82.","journal-title":"Clin. Immunol."},{"key":"e_1_3_2_5_2","first-page":"495","volume":"126","year":"1995","unstructured":"Casselman, B. L., K. S. Kilgore, B. F. Miller, and J. S. Warren. 1995. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J. Lab. Clin. Med.126:495-502.","journal-title":"J. Lab. Clin. Med."},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1038\/ni945","volume":"4","year":"2003","unstructured":"Chamaillard, M., M. Hashimoto, Y. Horie, J. Masumoto, S. Qiu, L. Saab, Y. Ogura, A. Kawasaki, K. Fukase, S. Kusumoto, M. A. Valvano, S. J. Foster, T. W. Mak, G. Nu\u00f1ez, and N. Inohara. 2003. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat. Immunol.4:702-707.","journal-title":"Nat. Immunol."},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/35025229","volume":"407","year":"2000","unstructured":"Coughlin, S. R. 2000. Thrombin signalling and protease-activated receptors. Nature407:258-264.","journal-title":"Nature"},{"key":"e_1_3_2_8_2","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1136\/bmj.285.6342.606","volume":"285","year":"1982","unstructured":"Davies, D. J., J. E. Moran, J. F. Niall, and G. B. Ryan. 1982. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br. Med. J. (clinical research ed.)285:606.","journal-title":"Br. Med. J. (clinical research ed.)"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"C1429","DOI":"10.1152\/ajpcell.1998.274.6.C1429","volume":"274","year":"1998","unstructured":"D\u00e9ry, O., C. U. Corvera, M. Steinhoff, and N. W. Bunnett. 1998. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am. J. Physiol.274:C1429-C1452.","journal-title":"Am. J. Physiol."},{"key":"e_1_3_2_10_2","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJM198806233182504","volume":"318","year":"1988","unstructured":"Falk, R. J., and J. C. Jennette. 1988. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N. Engl. J. Med.318:1651-1657.","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_2_11_2","doi-asserted-by":"crossref","first-page":"4115","DOI":"10.1073\/pnas.87.11.4115","volume":"87","year":"1990","unstructured":"Falk, R. J., R. S. Terrell, L. A. Charles, and J. C. Jennette. 1990. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc. Natl. Acad. Sci. USA87:4115-4119.","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1126\/science.1084677","volume":"300","year":"2003","unstructured":"Girardin, S. E., I. G. Boneca, L. A. M. Carneiro, A. Antignac, M. J\u00e9hanno, J. Viala, K. Tedin, M.-K. Taha, A. Labigne, U. Z\u00e4hringer, A. J. Coyle, P. S. DiStefano, J. Bertin, P. J. Sansonetti, and D. J. Philpott. 2003. Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science300:1584-1587.","journal-title":"Science"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200651200"},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1084\/jem.184.4.1567","volume":"184","year":"1996","unstructured":"Grimminger, F., K. Hattar, C. Papavassilis, B. Temmesfeld, E. Csernok, W. L. Gross, W. Seeger, and U. Sibelius. 1996. Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation. J. Exp. Med.184:1567-1572.","journal-title":"J. Exp. Med."},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1111\/j.1445-5994.1984.tb03769.x","volume":"14","year":"1984","unstructured":"Hall, J. B., B. M. Wadham, C. J. Wood, V. Ashton, and W. R. Adam. 1984. Vasculitis and glomerulonephritis: a subgroup with an antineutrophil cytoplasmic antibody. Aust. N. Z. J. Med.14:277-278.","journal-title":"Aust. N. Z. J. Med."},{"key":"e_1_3_2_16_2","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1189\/jlb.71.6.996","volume":"71","year":"2002","unstructured":"Hattar, K., A. Bickenbach, E. Csernok, S. Rosseau, U. Grandel, W. Seeger, F. Grimminger, and U. Sibelius. 2002. Wegener's granulomatosis: antiproteinase 3 antibodies induce monocyte cytokine and prostanoid release\u2014role of autocrine cell activation. J. Leukoc. Biol.71:996-1004.","journal-title":"J. Leukoc. Biol."},{"key":"e_1_3_2_17_2","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.4049\/jimmunol.168.6.3057","volume":"168","year":"2002","unstructured":"Hattar, K., U. Grandel, A. Bickenbach, A. Schwarting, W.-J. Mayet, J. Bux, S. Jessen, C. Fischer, W. Seeger, F. Grimminger, and U. Sibelius. 2002. Interaction of antibodies to proteinase 3 (classic anti-neutrophil cytoplasmic antibody) with human renal tubular epithelial cells: impact on signaling events and inflammatory mediator generation. J. Immunol.168:3057-3064.","journal-title":"J. Immunol."},{"key":"e_1_3_2_18_2","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1189\/jlb.0902442","volume":"78","year":"2005","unstructured":"Hattar, K., S. van B\u00fcrck, A. Bickenbach, U. Grandel, U. Maus, J. Lohmeyer, E. Csernok, T. Hartung, W. Seeger, F. Grimminger, and U. Sibelius. 2005. Anti-proteinase 3 antibodies (c-ANCA) prime CD14-dependent leukocyte activation. J. Leukoc. Biol.78:992-1000.","journal-title":"J. Leukoc. Biol."},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1126\/science.284.5418.1313","volume":"284","year":"1999","unstructured":"Hoffmann, J. A., F. C. Kafatos, C. A. Janeway, Jr., and R. A. B. Ezekowitz. 1999. Phylogenetic perspectives in innate immunity. Science284:1313-1318.","journal-title":"Science"},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"5509","DOI":"10.1074\/jbc.C200673200","volume":"278","year":"2003","unstructured":"Inohara, N., Y. Ogura, A. Fontalba, O. Gutierrez, F. Pons, J. Crespo, K. Fukase, S. Inamura, S. Kusumoto, M. Hashimoto, S. J. Foster, A. P. Moran, J. L. Fernandez-Luna, and G. Nu\u00f1ez. 2003. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease. J. Biol. Chem.278:5509-5512.","journal-title":"J. Biol. Chem."},{"key":"e_1_3_2_21_2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1146\/annurev.immunol.20.083001.084359","volume":"20","year":"2002","unstructured":"Janeway, C. A., Jr., and R. Medzhitov. 2002. Innate immune recognition. Annu. Rev. Immunol.20:197-216.","journal-title":"Annu. Rev. Immunol."},{"key":"e_1_3_2_22_2","first-page":"520","volume":"346","year":"1990","unstructured":"Jenne, D. E., J. Tschopp, J. L\u00fcdemann, B. Utecht, and W. L. Gross. 1990. Wegener's autoantigen decoded. Nature346:520.","journal-title":"Nature"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1093\/ndt\/14.6.1366","volume":"14","year":"1999","unstructured":"Muller Kobold, A. C., Y. M. van der Geld, P. C. Limburg, J. W. C. Tervaert, and C. G. M. Kallenberg. 1999. Pathophysiology of ANCA-associated glomerulonephritis. Nephrol. Dial. Transplant.14:1366-1375.","journal-title":"Nephrol. Dial. Transplant."},{"key":"e_1_3_2_24_2","first-page":"369","volume":"16","year":"1997","unstructured":"Novo, E., E. G.-M. Gregor, S. Nava, and L. Perini. 1997. A possible defective estimation of antineutrophil cytoplasmic antibodies in systemic lupus erythematosus due to the coexistence of periodontitis: preliminary observations. P. R. Health Sci. J.16:369-373.","journal-title":"P. R. Health Sci. J."},{"key":"e_1_3_2_25_2","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/sj.onc.1204194","volume":"20","year":"2001","unstructured":"O'Brien, P. J., M. Molino, M. Kahn, and L. F. Brass. 2001. Protease activated receptors: theme and variations. Oncogene20:1570-1581.","journal-title":"Oncogene"},{"key":"e_1_3_2_26_2","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1172\/JCI119662","volume":"100","year":"1997","unstructured":"Ralston, D. R., C. B. Marsh, M. P. Lowe, and M. D. Wewers. 1997. Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, \u03b11-antitrypsin, and Fc\u03b3 receptors. J. Clin. Investig.100:1416-1424.","journal-title":"J. Clin. Investig."},{"key":"e_1_3_2_27_2","first-page":"335","volume":"141","year":"1992","unstructured":"Savage, C. O. S., B. E. Pottinger, G. Gaskin, C. D. Pusey, and J. D. Pearson. 1992. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am. J. Pathol.141:335-342.","journal-title":"Am. J. Pathol."},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1001\/archinte.1989.00390110055012","volume":"149","year":"1989","unstructured":"Tervaert, J. W., F. J. van der Woude, A. S. Fauci, J. L. Ambrus, J. Velosa, W. F. Keane, S. Meijer, M. van der Giessen, G. K. van der Hem, T. H. The, et al. 1989. Association between active Wegener's granulomatosis and anticytoplasmic antibodies. Arch. Intern. Med.149:2461-2465.","journal-title":"Arch. Intern. Med."},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1016\/j.molimm.2007.02.007","volume":"44","year":"2007","unstructured":"Uehara, A., Y. Fujimoto, K. Fukase, and H. Takada. 2007. Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol. Immunol.44:3100-3111.","journal-title":"Mol. Immunol."},{"key":"e_1_3_2_30_2","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.4049\/jimmunol.177.3.1796","volume":"177","year":"2006","unstructured":"Uehara, A., Y. Fujimoto, A. Kawasaki, S. Kusumoto, K. Fukase, and H. Takada. 2006. Meso-diaminopimelic acid and meso-lanthionine, amino acids specific to bacterial peptidoglycans, activate human epithelial cells through NOD1. J. Immunol.177:1796-1804.","journal-title":"J. Immunol."},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1016\/j.molimm.2007.03.010","volume":"44","year":"2007","unstructured":"Uehara, A., A. Iwashiro, T. Sato, S. Yokota, and H. Takada. 2007. Antibodies to proteinase 3 prime human monocytic cells via protease-activated receptor-2 and NF-\u03baB for Toll-like receptor- and NOD-dependent activation. Mol. Immunol.44:3552-3562.","journal-title":"Mol. Immunol."},{"key":"e_1_3_2_32_2","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.4049\/jimmunol.173.6.4179","volume":"173","year":"2004","unstructured":"Uehara, A., Y. Sugawara, T. Sasano, H. Takada, and S. Sugawara. 2004. Proinflammatory cytokines induce proteinase 3 as membrane-bound and secretory forms in human oral epithelial cells and antibodies to proteinase 3 activate the cells through protease-activated receptor-2. J. Immunol.173:4179-4189.","journal-title":"J. Immunol."},{"key":"e_1_3_2_33_2","first-page":"425","volume":"1","year":"1985","unstructured":"van der Woude, F. J., N. Rasmussen, S. Lobatto, A. Wiik, H. Permin, L. A. van Es, M. van der Giessen, G. K. van der Hem, and T. H. The. 1985. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet1:425-429.","journal-title":"Lancet"},{"key":"e_1_3_2_34_2","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1136\/ard.33.6.515","volume":"33","year":"1974","unstructured":"Wiik, A., E. Jensen, and J. Friis. 1974. Granulocyte-specific antinuclear factors in synovial fluids and sera from patients with rheumatoid arthritis. Ann. Rheum. Dis.33:515-522.","journal-title":"Ann. Rheum. Dis."}],"container-title":["Clinical and Vaccine Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/CVI.00137-08","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/CVI.00137-08","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T13:13:12Z","timestamp":1684415592000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/CVI.00137-08"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,7]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2008,7]]}},"alternative-id":["10.1128\/CVI.00137-08"],"URL":"https:\/\/doi.org\/10.1128\/cvi.00137-08","relation":{},"ISSN":["1556-6811","1556-679X"],"issn-type":[{"value":"1556-6811","type":"print"},{"value":"1556-679X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,7]]},"assertion":[{"value":"2008-04-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-05-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-12-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}