ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.
Viral infections and abnormal host response are thought to cause epithelial injury in idiopathic pulmonary fibrosis (IPF). To understand IPF pathogenesis, we have used overexpression cell models and expression microarrays to discover genes networked with ELMO domain containing 2 (ELMOD2) gene genetically implicated in IPF. The identified pathways were confirmed in vitro, and ELMOD2 protein expression was characterized in tissue samples. Here 303 genes were significantly altered after ELMOD2 transfection of human alveolar epithelial A549 cell line. The enriched pathways were interferon induction, viral response, antigen processing and presentation, and I-/nuclear factor-kappaB signaling. ELMOD2 showed immunoreactivity in macrophages and type II alveolar epithelial cells in normal human lung. In A549 cells, forced expression of ELMOD2 increased type I and type III interferon mRNA expression, and ELMOD2-specific siRNA molecules inhibited expression of these antiviral cytokines in response to Toll-like receptor three (TLR3) activation. In human macrophages silencing of ELMOD2 inhibited TLR3-dependent expression of type I and type III interferon genes. Influenza A virus infection decreased ELMOD2 mRNA expression in A549 cells and macrophages suggesting negative regulation in viral infections. In summary, our results show that TLR3 pathway is dependent on ELMOD2.-Pulkkinen, V., Bruce, S., Rintahaka, J., Hodgson, U., Laitinen, T., Alenius, H., Kinnula, V. L., Myllärniemi, M., Matikainen, S., Kere, J. ELMOD2, a candidate gene for idiopathic pulmonary fibrosis, regulates antiviral responses.
Pulkkinen
Ville
V
Department of Medical Genetics, Biomedicum Helsinki, P.O. Box 63, 00014 University of Helsinki, Finland. ville.pulkkinen@helsinki.fi
Bruce
Sara
S
Rintahaka
Johanna
J
Hodgson
Ulla
U
Laitinen
Tarja
T
Alenius
Harri
H
Kinnula
Vuokko L
VL
Myllärniemi
Marjukka
M
Matikainen
Sampsa
S
Kere
Juha
J
D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology
D003598:Cytoskeletal Proteins; C512339:ELMOD2 protein, human; D016328:NF-kappa B; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3