title: Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine.
abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.
authors.affiliation: Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.|Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Department of Pulmonary Medicine, Helsinki, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Sutinen
authors.affiliation: Department of Pathology, University of Helsinki and Fimlab laboratories, Pathology, Tampere, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Rönty
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: Unit of Systems Toxicology and Nanosafety Centre, Finnish Institute of Occupational Health (FIOH), Helsinki, Finland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Fortino
authors.affiliation: University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Department of Pulmonary Medicine, Helsinki, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Pulkkinen
authors.affiliation: Unit of Systems Toxicology and Nanosafety Centre, Finnish Institute of Occupational Health (FIOH), Helsinki, Finland.
authors.forename: Dario
authors.initials: D
authors.lastname: Greco
authors.affiliation: Department of Physiology, Institute of Biomedicine and Turku Center for Disease Modeling, University of Turku, Turku, Finland.
authors.forename: Petra
authors.initials: P
authors.lastname: Sipilä
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.|University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Department of Pulmonary Medicine, Helsinki, Finland.
authors.forename: Marjukka
authors.initials: M
authors.lastname: Myllärniemi
mesh_terms: D000818:Animals; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000032:analysis / Q000276:immunology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics*; D007372:Interferons / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012822:Silicon Dioxide / Q000276:immunology; D015854:Up-Regulation; D016207:Cytokines
chemical_list: D054357:Chemokine CXCL10; D036341:Intercellular Signaling Peptides and Proteins; D007372:Interferons; D012822:Silicon Dioxide; C486399:GREM1 protein, human; C113178:Grem1 protein, mouse; D016207:Cytokines