Cigarette smoke decreases innate responses of epithelial cells to rhinovirus infection.
Exposure to cigarette smoke is associated with a significant increase in the risk for respiratory viral infections. The airway epithelium is the primary target for both cigarette smoke and respiratory viral infection. We investigated the effects of cigarette smoke on the response of airway epithelial cells to rhinovirus infection. We found that pre-exposure of BEAS-2B cells or primary normal human bronchial epithelial cells (NHBEs) to cigarette smoke extract (CSE) reduced the induction of mRNA of the chemokines CXCL10 and CCL5 by either the viral mimic polyinosine-polycytidylic acid (Poly I:C) or human rhinovirus 16 (HRV-16) infection. The HRV-16-induced release of CXCL10 and CCL5 was also significantly suppressed by CSE. Activation of the IFN mediator STAT-1 and the activation of JNK by poly I:C and HRV-16 were partially suppressed by pre-exposure to CSE. In contrast, the poly I:C-induced and HRV-16-induced phosphorylation of ERK1/2 was unaffected by CSE. HRV-16-stimulated IFN-β mRNA was also significantly reduced by CSE. Because suppression of the IFN response to viral infection was associated with increased viral production, we assessed HRV-16 RNA concentrations. Exposure to CSE resulted in an increase in HRV-16 RNA at 48 hours after the infection of BEAS-2B cells. These data demonstrate that exposure to CSE alters the response of airway epithelial cells to HRV infection, leading to decreased activation of the IFN-STAT-1 and SAP-JNK pathways, the suppression of CXCL10 and CCL5 production, and increased viral RNA. A diminished, early epithelial-initiated antiviral response to rhinovirus infection could contribute to the increased susceptibility of subjects to prolonged respiratory viral infections after exposure to cigarette smoke.
Eddleston
Jane
J
Veterans Medical Research Foundation, and Department of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0732, USA. jeddleston@vapop.ucsd.edu
Lee
Rachel U
RU
Doerner
Astrid M
AM
Herschbach
Jack
J
Zuraw
Bruce L
BL
D002460:Cell Line; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011070:Poly I-C / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000821:virology; D012229:Rhinovirus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013997:Time Factors; D019562:Viral Load; D014779:Virus Replication
C483024:CCL5 protein, human; C114753:CXCL10 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D012333:RNA, Messenger; D012367:RNA, Viral; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D012906:Smoke; D016899:Interferon-beta; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D011070:Poly I-C