title: T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-gamma and IL-13 production.
abstract: We previously reported that ovalbumin (OVA) and IL-18 nasally administered act on memory type T helper (Th)1 cells to induce airway hyperresponsiveness (AHR) and inflammation, which is characterized by peribronchial infiltration with neutrophils and eosinophils. Here, we report this administration also induces lung fibrosis in an IL-13-dependent manner. Th1 cells secrete several cytokines, including IFN-gamma and bronchogenic cytokine IL-13, when stimulated with antigen (Ag) and IL-18. However, IL-13 blockade failed to attenuate AHR, although this treatment inhibited eosinophilic infiltration. To understand the mechanism by which Th1 cells induce AHR after Ag plus IL-18 challenge, we established "passive" and "active" Th1 mice by transferring OVA-specific Th1 cells into naïve BALB/c mice or by immunizing naïve BALB/c mice with OVA/complete Freund's adjuvant, respectively. Administration of Ag and IL-18 induced both types of Th1 mice to develop AHR, airway inflammation, and lung fibrosis. Furthermore, this treatment induced deposition of periostin, a novel component of lung fibrosis. Neutralization of IL-13 or IFN-gamma during Ag plus IL-18 challenges inhibited the combination of eosinophilic infiltration, lung fibrosis, and periostin deposition or the combination of neutrophilic infiltration and AHR, respectively. We also found that coadministration of OVA and LPS into Th1 mice induced AHR and airway inflammation via endogenous IL-18. Thus, IL-18 becomes a key target molecule for the development of a therapeutic regimen for the treatment of Th1-cell-induced bronchial asthma.
authors.affiliation: Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Izuhara
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsui
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015815:Cell Adhesion Molecules; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D005620:Freund's Adjuvant / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000096:biosynthesis*; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D015815:Cell Adhesion Molecules; D018793:Interleukin-13; D020382:Interleukin-18; D008070:Lipopolysaccharides; C082838:Postn protein, mouse; D007371:Interferon-gamma; D010047:Ovalbumin; D005620:Freund's Adjuvant