title: Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells.
abstract: Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, United States of America; Department of Pathology, Immunology and Microbiology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Oslund
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Boram
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Lingxiang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, United States of America; Department of Pathology, Immunology and Microbiology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America.
authors.forename: Trang
authors.initials: T
authors.lastname: Duong
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Shih
authors.affiliation: Department of Pathology, Immunology and Microbiology, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Baumgarth
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Li-Yin
authors.initials: LY
authors.lastname: Hung
authors.affiliation: Center for Comparative Respiratory Biology and Medicine, Department of Internal Medicine, University of California Davis, Davis, California, United States of America.
authors.forename: Reen
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D007370:Interferon Type I / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012330:RNA, Double-Stranded / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000821:virology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007370:Interferon Type I; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma