Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells.
Mucus hypersecretion is a prominent manifestation in patients with chronic inflammatory airway diseases. MUC5AC mucin is a major component of airway mucus, and its expression is modulated by a TNF-alpha-converting enzyme (TACE)-EGF receptor pathway that can be activated by reactive oxygen species (ROS). Dual oxidase 1 (Duox1), a homologue of glycoprotein p91(phox), is expressed in airway epithelium and generates ROS. We hypothesize that Duox1 activates TACE, cleaving pro-TGF-alpha into soluble TGF-alpha, resulting in mucin expression. To examine this hypothesis, we stimulated both normal human bronchial epithelial cells and NCI-H292 airway epithelial cells with phorbol 12-myristate 13-acetate and with human neutrophil elastase. These stimuli induced TACE activation, TGF-alpha release, and mucin expression, effects that were inhibited by ROS scavengers, implicating ROS in TACE activation. Inhibition of epithelial NADPH oxidase or knockdown of Duox1 expression with small interfering RNA prevented ROS generation, TGF-alpha release, and mucin expression by these stimuli, implicating Duox1 in TACE activation and mucin expression. Furthermore, the PKCdelta/PKC inhibitor rottlerin prevented the effects induced by phorbol 12-myristate 13-acetate and human neutrophil elastase, suggesting that PKCdelta and PKC are involved in Duox1 activation. From these results, we conclude that Duox1 plays a critical role in mucin expression by airway epithelial cells through PKCdelta/PKC-Duox1-ROS-TACE-pro-ligand-EGF receptor cascade.
Shao
Matt X G
MX
Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, CA 94143-0130, USA.
Nadel
Jay A
JA
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D002478:Cells, Cultured; D000074623:Dual Oxidases; D004847:Epithelial Cells; D005420:Flavoproteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D019272:Leukocyte Elastase / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000378:metabolism*; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics*; D019255:NADPH Oxidases / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051745:Protein Kinase C-delta; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000378:metabolism
D005420:Flavoproteins; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D017382:Reactive Oxygen Species; D016211:Transforming Growth Factor alpha; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C431513:DUOX1 protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D019272:Leukocyte Elastase; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D013755:Tetradecanoylphorbol Acetate