Stimulation of the RIG-I/MAVS Pathway by Polyinosinic:Polycytidylic Acid Upregulates IFN-β in Airway Epithelial Cells with Minimal Costimulation of IL-8.
Pharmacological stimulation of the antiviral cytokine IFN-β in the airways may help to counter deleterious virus-induced exacerbations in chronic inflammatory lung diseases (asthma, chronic obstructive pulmonary disease, or cystic fibrosis). Polyinosinic-polycytidylic acid [poly(I:C)] is a known inducer of IFN-β but also costimulates an inflammatory response. The latter response is undesirable given the pre-existing airway inflammation in these diseases. The objective of our study was to identify conditions for poly(I:C) to selectively upregulate IFN-β in airway epithelial cells without a concomitant inflammatory response. The inflammatory response was gauged by production of the chemokine IL-8. Using cell lines and primary airway epithelial cells (both submerged and well-differentiated), we observed that pure poly(I:C) stimulated IFN-β mainly through the TLR3/TRIF pathway and IL-8 through an unidentified pathway. The magnitude of the IL-8 response stimulated by pure poly(I:C) matched or even exceeded that of IFN-β. Furthermore, this IL-8 response could not be pharmacologically downregulated without affecting IFN-β. In contrast, we show that stimulation of the RIG-I/MAVS pathway, such as when poly(I:C) is delivered intracellularly in a complex with liposomes or via nucleofection, selectively stimulates IFN-β with low IL-8 costimulation. The magnitude of IFN-β stimulation by liposome-encapsulated poly(I:C) is markedly diminished in well-differentiated cells. In conclusion, it is feasible to augment IFN-β production in airway epithelial cells without excessive costimulation of IL-8 if the RIG-I/MAVS pathway is stimulated, such as via liposomal delivery of poly(I:C). Better cytoplasmic delivery vehicles are needed to efficiently stimulate this pathway in well-differentiated cells.
The Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; and nurlan.dauletbaev@mail.mcgill.ca larry.lands@mcgill.ca.
Nurlan
N
Dauletbaev
The Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; and.
Maria
M
Cammisano
The Research Institute of McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada; and.
Kassey
K
Herscovitch
Respiratory Medicine, Montreal Children's Hospital, Montreal, Quebec H4A 3J1, Canada nurlan.dauletbaev@mail.mcgill.ca larry.lands@mcgill.ca.
Larry C
LC
Lands
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology*; D011971:Receptors, Immunologic; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C508606:CXCL8 protein, human; D016209:Interleukin-8; C505371:MAVS protein, human; D011971:Receptors, Immunologic; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011070:Poly I-C