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Am J Respir Cell Mol Biol. 2012 Mar 1. [Epub ahead of print]
Influenza A induces the major secreted airway mucin MUC5AC in a protease-EGFR-ERK-Sp1 dependent pathway.
Barbier D, Garcia-Verdugo I, Pothlichet J, Khazen R, Descamps D, Rousseau K, Thornton D, Si-Tahar M, Touqui L, Chignard M, Sallenave JM.
Source
Unit? D?fense Inn?e et Inflammation, Institut Pasteur, Paris, France.
Abstract
Rationale : Mucins, the main glycoproteins present within mucus, modulate rheologic properties of airways and participate in lung defense. They are thought to be able to trap and eliminate micro-organisms from the lung. Among the mucins secreted in the lung, MUC5AC is the most prominent factor secreted by surface epithelial cells. Objectives : Although much is known about the signaling pathways involved in MUC5AC regulation by host factors such as cytokines or proteases, less is known about the pathways triggered by micro-organisms and specifically, by influenza A virus (IAV). We therefore set up to dissect the molecular mechanisms responsible for the potential modulation of MUC5AC by IAV. Methods : Using epithelial cells, C57/Bl6 mice, and IAV strains, we measured MUC5AC expression at the RNA and protein levels, Sp1 activation and protease activity. Intermediate molecular partners were confirmed using pharmacological inhibitors, blocking antibodies, and si RNAs. Measurements and main Results : We showed in vitro and in vivo, that IAV up-regulates epithelial cell-derived MUC5AC and Muc5ac expression in mice, both at transcriptional (through Sp1 induction) and translational levels. In addition, we determined that this induction was dependent upon a protease-EGFR-ERK-Sp1 signalling cascade, involving in particular the human airway trypsin (HAT). Conclusion : Our data point to MUC5AC as a potential modulatory mechanism by which the lung epithelium respond to IAV infection, and dissect, for the first time, the molecular partners involved. Future experiments using MUC5AC-targeted strategies should help to further unravel the pathophysiological consequences of IAV-induced MUC5AC expression for lung homeostasis.
PMID:
22383584
[PubMed - as supplied by publisher]
Influenza A induces the major secreted airway mucin MUC5AC in a protease-EGFR-ERK-Sp1 dependent pathway.
Barbier D, Garcia-Verdugo I, Pothlichet J, Khazen R, Descamps D, Rousseau K, Thornton D, Si-Tahar M, Touqui L, Chignard M, Sallenave JM.
Source
Unit? D?fense Inn?e et Inflammation, Institut Pasteur, Paris, France.
Abstract
Rationale : Mucins, the main glycoproteins present within mucus, modulate rheologic properties of airways and participate in lung defense. They are thought to be able to trap and eliminate micro-organisms from the lung. Among the mucins secreted in the lung, MUC5AC is the most prominent factor secreted by surface epithelial cells. Objectives : Although much is known about the signaling pathways involved in MUC5AC regulation by host factors such as cytokines or proteases, less is known about the pathways triggered by micro-organisms and specifically, by influenza A virus (IAV). We therefore set up to dissect the molecular mechanisms responsible for the potential modulation of MUC5AC by IAV. Methods : Using epithelial cells, C57/Bl6 mice, and IAV strains, we measured MUC5AC expression at the RNA and protein levels, Sp1 activation and protease activity. Intermediate molecular partners were confirmed using pharmacological inhibitors, blocking antibodies, and si RNAs. Measurements and main Results : We showed in vitro and in vivo, that IAV up-regulates epithelial cell-derived MUC5AC and Muc5ac expression in mice, both at transcriptional (through Sp1 induction) and translational levels. In addition, we determined that this induction was dependent upon a protease-EGFR-ERK-Sp1 signalling cascade, involving in particular the human airway trypsin (HAT). Conclusion : Our data point to MUC5AC as a potential modulatory mechanism by which the lung epithelium respond to IAV infection, and dissect, for the first time, the molecular partners involved. Future experiments using MUC5AC-targeted strategies should help to further unravel the pathophysiological consequences of IAV-induced MUC5AC expression for lung homeostasis.
PMID:
22383584
[PubMed - as supplied by publisher]
