title: Transcriptional and epigenetic modulation of human rhinovirus-induced CXCL10 production by cigarette smoke.
abstract: Human rhinovirus (HRV) triggers exacerbations of asthma and chronic obstructive pulmonary disease. Cigarette smoking is the primary risk factor for the development of chronic obstructive pulmonary disease, and 25% of individuals with asthma smoke. Smokers experience both longer and more severe colds. We previously showed that cigarette smoke extract (CSE) inhibited HRV-induced expression of a range of epithelial antiviral molecules. Here, we use CXCL10 as a model antiviral gene to examine the mechanisms by which CSE inhibits epithelial antiviral immunity. HRV-induced CXCL10 transcription depends on activation of NF-ĸB and IFN-regulatory factor-1 (IRF-1), and we now also implicate two signal transducer and activator of transcription (STAT) consensus sequences in the CXCL10 promoter in HRV-induced CXCL10 expression. CSE inhibited HRV-induced activation and nuclear translocation/binding of both NF-ĸB, and IRF-1 to their respective recognition sequences in the CXCL10 promoter. HRV also induced formation of complexes at the STAT region in the CXCL10 promoter, and HRV-induced activation of STAT-1 was inhibited by CSE. In addition, CSE inhibited HRV-induced chromatin accessibility around the transcriptional start site of the CXCL10 promoter. Although CSE inhibited HRV-induced expression of both the viral double-stranded RNA sensors, retinoic acid-inducible gene-I and melanoma differentiation-associated gene (MDA) 5, only specific short interfering RNA (siRNA) to MDA5, but not nontargeting siRNA, or siRNA to retinoic acid-inducible gene-I, inhibited HRV-induced CXCL10 induction. We conclude that CSE reduces chromatin accessibility and inhibits viral signaling via NF-ĸB, IRF-1, STAT-1, and MDA5. Thus, we show that CSE can simultaneously modulate multiple pathways linked to innate immune responses to HRV infection.
authors.affiliation: Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, University of Calgary, Faculty of Medicine, Calgary, Alberta, Canada.
authors.forename: Magdalena H
authors.initials: MH
authors.lastname: Hudy
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Traves
authors.forename: David
authors.initials: D
authors.lastname: Proud
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012229:Rhinovirus / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D012906:Smoke; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1