title: Chronic Fibro-Inflammatory Responses in Autoimmune Pancreatitis Depend on IFN-α and IL-33 Produced by Plasmacytoid Dendritic Cells.
abstract: In previous studies, we found that human IgG4-related autoimmune pancreatitis (AIP) and murine AIP are driven by activation of plasmacytoid dendritic cells (pDCs) producing IFN-α. In the present studies we examined additional roles of pDC-related mechanisms in AIP pathogenesis, particularly those responsible for induction of fibrosis. We found that in murine AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid) not only the pancreatic infiltration of immune cells but also the development of fibrosis were markedly reduced by the depletion of pDCs or blockade of type I IFN signaling; moreover, such treatment was accompanied by a marked reduction of pancreatic expression of IL-33. Conversely, polyinosinic-polycytidylic acid-induced inflamed pancreatic tissue in murine AIP exhibited increased expression of type I IFNs and IL-33 (and downstream IL-33 cytokines such as IL-13 and TGF-β1). pDCs stimulated by type I IFN were the source of the IL-33 because purified populations of these cells isolated from the inflamed pancreas produced a large amount of IL-33 upon activation by TLR9 ligands, and such production was abrogated by the neutralization of type I IFN. The role of IL-33 in murine AIP pathogenesis was surprisingly important because blockade of IL-33 signaling by anti-ST2 Ab attenuated both pancreatic inflammation and accompanying fibrosis. Finally, whereas patients with both conventional pancreatitis and IgG4-related AIP exhibited increased numbers of acinar cells expressing IL-33, only the latter also exhibited pDCs producing this cytokine. These data thus suggest that pDCs producing IFN-α and IL-33 play a pivotal role in the chronic fibro-inflammatory responses underlying murine AIP and human IgG4-related AIP.
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan; tomohiro@med.kindai.ac.jp tmhrwtnb@kuhp.kyoto-u.ac.jp.|Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Minaga
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kamata
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Yoriaki
authors.initials: Y
authors.lastname: Komeda
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takenaka
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ida
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Nishida
authors.affiliation: Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
authors.affiliation: Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D061354:Acinar Cells / Q000276:immunology; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000503:physiopathology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005355:Fibrosis / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000276:immunology / Q000473:pathology; D010195:Pancreatitis / Q000276:immunology* / Q000503:physiopathology; D011070:Poly I-C / Q000008:administration & dosage; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: C506536:IL33 protein, human; D007074:Immunoglobulin G; D016898:Interferon-alpha; D000067596:Interleukin-33; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D011070:Poly I-C