Rhinovirus induces MUC5AC in a human infection model and in vitro via NF-κB and EGFR pathways.
Rhinovirus (RV) infections are the major cause of asthma exacerbations, the major cause of morbidity and mortality in asthma. MUC5AC is the major mucin produced by bronchial epithelial cells. Whether RV infection upregulates MUC5AC in vivo is unknown and the molecular mechanisms involved are incompletely understood. We investigated RV induction of MUC5AC in vivo and in vitro to identify targets for development of new therapies for asthma exacerbations. RV infection increased MUC5AC release in normal and asthmatic volunteers experimentally infected with RV-16, and in asthmatic, but not normal, subjects, this was related to virus load. Bronchial epithelial cells were confirmed a source of MUC5AC in vivo. RV induction of MUC5AC in bronchial epithelial cells in vitro occurred via nuclear factor-κB-dependent induction of matrix metalloproteinase-mediated transforming growth factor-α release, thereby activating an epidermal growth factor receptor-dependent cascade culminating, via mitogen-activated protein kinase activation, in specificity protein-1 transactivation of the MUC5AC promoter. RV induction of MUC5AC may be an important mechanism in RV-induced asthma exacerbations in vivo. Revealing the complex serial signalling cascade involved identifies targets for development of pharmacologic intervention to treat mucus hypersecretion in RV-induced illness.
Dept of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, Norfolk Place, London, W2 1PG, UK.
C A
CA
Hewson
J J
JJ
Haas
N W
NW
Bartlett
S D
SD
Message
V
V
Laza-Stanca
T
T
Kebadze
G
G
Caramori
J
J
Zhu
M R
MR
Edbrooke
L A
LA
Stanciu
O M
OM
Kon
A
A
Papi
P K
PK
Jeffery
M R
MR
Edwards
S L
SL
Johnston
D000328:Adult; D001249:Asthma / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001980:Bronchi / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D055271:Mucin 5AC / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010850:Picornaviridae Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D011401:Promoter Regions, Genetic; D012229:Rhinovirus / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D015854:Up-Regulation; D019562:Viral Load
C524678:MUC5AC protein, human; D055271:Mucin 5AC; D016328:NF-kappa B; D016329:Sp1 Transcription Factor; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases