The Signaling Pathway Involved in Neutrophil Elastase–Stimulated MUC1 Transcription
- 1 December 2007
- journal article
- Published by American Thoracic Society in American Journal of Respiratory Cell and Molecular Biology
- Vol. 37 (6), 691-698
- https://doi.org/10.1165/rcmb.2007-0072oc
Abstract
We previously reported that neutrophil elastase (NE) stimulated MUC1 gene expression in A549 lung epithelial cells through binding of Sp1 to the MUC1 promoter element. The current study was undertaken to elucidate the complete signaling pathway leading to Sp1 activation. Using a combination of pharmacologic inhibitors, dominant-negative mutant, RNA interference, and soluble receptor blocking techniques, we identified a protein kinase Cdelta (PKCdelta) --> dual oxidase 1 (Duox1) --> reactive oxygen species (ROS) --> TNF-alpha-converting enzyme (TACE) --> TNF-alpha --> TNF receptor (TNFR)1 --> extracellular signal-regulated kinase (ERK)1/2 --> Sp1 pathway as responsible for NE-activated MUC1 transcription. This cascade was identical up to the point of TACE with the signaling pathway previously reported for NE-stimulated MUC5AC production. However, unlike the MUC5AC pathway, TNF-alpha, TNFR1, ERK1/2, and Sp1 were unique components of the MUC1 pathway. Given the anti-inflammatory role of MUC1 during airway bacterial infection, up-regulation of MUC1 by inflammatory mediators such as NE and TNF-alpha suggests a crucial role for MUC1 in the control of excessive inflammation during airway bacterial infection.Keywords
This publication has 56 references indexed in Scilit:
- Tumor Necrosis Factor-α Triggers Mucus Production in Airway Epithelium through an IκB Kinase β-dependent MechanismJournal of Biological Chemistry, 2005
- Neutrophil elastase stimulatesMUC1gene expression through increased Sp1 binding to theMUC1promoterAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2005
- Neutrophil elastase induces mucus cell metaplasia in mouse lungAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2004
- PMA Induces the MUC5AC Respiratory Mucin in Human Bronchial Epithelial Cells, via PKC, EGF/TGF-α, Ras/Raf, MEK, ERK and Sp1-dependent MechanismsJournal of Molecular Biology, 2004
- Extracellular signal-regulated kinase is involved in tumor necrosis factor-α-inducedMUC5ACgene expression in cultured human nasal polyp epithelial cellsActa Oto-Laryngologica, 2004
- The Sp1 Transcription Factor Regulates Cell Type-Specific Transcription of MUC1DNA and Cell Biology, 2001
- A STAT-responsive Element in the Promoter of the Episialin/MUC1 Gene Is Involved in Its Overexpression in Carcinoma CellsJournal of Biological Chemistry, 2001
- Immunocytochemical evidence for extra-cellular initiation of elastase-induced bronchial secretory cell metaplasia in hamstersEuropean Respiratory Journal, 1996
- Rottlerin, a Novel Protein Kinase InhibitorBiochemical and Biophysical Research Communications, 1994
- Evaluation of Elastase and α1-Proteinase Inhibitor-Elastase Uptake by Polymorphonuclear Leukocytes and Evidence of an Elastase-Specific Receptorcclm, 1986