title: Role of Chitinase 3-Like-1 in Interleukin-18-Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung.
abstract: Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic chitinase-like protein. Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation and the magnitude of tissue injury and fibroproliferative repair. This can be appreciated in studies that highlight its induction after cigarette smoke exposure, during which it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke, and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate chronic obstructive pulmonary disease-like inflammation, fibrosis, and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild-type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ-, IL-13-, and IL-17A-dependent mechanisms. The latter studies demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced type 2 and type 17 inflammation and fibrotic airway remodeling were significantly ameliorated, whereas type 1 inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte perforin, granzyme, and retinoic acid early transcript 1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18-induced inflammatory, fibrotic, alveolar remodeling, and cytotoxic responses.
authors.affiliation: 1 Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut.|2 Departments of Molecular Microbiology and Immunology, and Medicine, Brown University, Providence, Rhode Island; and.
authors.forename: Min-Jong
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: 1 Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut.|2 Departments of Molecular Microbiology and Immunology, and Medicine, Brown University, Providence, Rhode Island; and.
authors.forename: Chang Min
authors.initials: CM
authors.lastname: Yoon
authors.affiliation: 1 Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut.|2 Departments of Molecular Microbiology and Immunology, and Medicine, Brown University, Providence, Rhode Island; and.
authors.forename: Milang
authors.initials: M
authors.lastname: Nam
authors.affiliation: 3 Department of Life Science, Research Institute for Natural Sciences, and.|4 Hanyang Biomedical Research Institute, Hanyang University, Seoul, Republic of Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: 3 Department of Life Science, Research Institute for Natural Sciences, and.|4 Hanyang Biomedical Research Institute, Hanyang University, Seoul, Republic of Korea.
authors.forename: Je-Min
authors.initials: JM
authors.lastname: Choi
authors.affiliation: 2 Departments of Molecular Microbiology and Immunology, and Medicine, Brown University, Providence, Rhode Island; and.
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.affiliation: 1 Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut.|2 Departments of Molecular Microbiology and Immunology, and Medicine, Brown University, Providence, Rhode Island; and.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D000071451:Chitinase-3-Like Protein 1; D003602:Cytotoxicity, Immunologic; D006023:Glycoproteins / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011656:Pulmonary Emphysema / Q000276:immunology / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D020382:Interleukin-18
keywords: COPD; Chi3l1; IL-18; airway fibrosis; alveolar remodeling