Abstract
Notch1 is an evolutionarily conserved receptor that regulates cell fate, including such events as differentiation, proliferation, and apoptosis. Myofibroblast differentiation is a key feature of lung fibrosis. Found in inflammatory zone 1 (FIZZ1) has direct fibrogenic properties because of its ability to induce myofibroblast differentiation. However, the downstream signaling pathway that mediates FIZZ1 induction of myofibroblast differentiation remains unknown. The objective of this study was to investigate the involvement of Notch signaling in FIZZ1 induction of lung myofibroblast differentiation and thus explore the potential role of Notch1 in pulmonary fibrosis. The results showed that FIZZ1 increased the expression levels of activated intracellular domain of Notch1 (NIC), its ligand Jagged1, and its target gene Hes1, which were associated with elevated alpha-smooth muscle actin expression levels. Fibroblast alpha-smooth muscle actin expression is induced by the overexpression of NIC but is suppressed by the inhibition of NIC. Moreover, lung fibroblasts that were isolated from mice lacking the GDP-4-keto-6-deoxymannose3,5-epimerase-4-reductase enzyme (FX knockout) exhibited significantly reduced responsiveness to FIZZ1, which was reversed by fucose supplementation. In the absence of exogenous fucose, these FX-deficient cells exhibited defective fucosylation, which is required for Notch signaling. These knockout mice also showed impaired lung fibrosis. These findings suggest that Notch1 signaling in response to FIZZ1 may play a significant role in myofibroblast differentiation during lung fibrosis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Animals
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Antibiotics, Antineoplastic / toxicity
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Bleomycin / toxicity
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Blotting, Western
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Calcium-Binding Proteins / antagonists & inhibitors
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cell Differentiation*
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Fibroblasts / cytology*
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Fibroblasts / metabolism
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Fluorescent Antibody Technique
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Fucose / administration & dosage
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Hydro-Lyases / physiology
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Hydroxyproline / metabolism
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Lung / cytology*
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Lung / metabolism
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle, Smooth / cytology
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Muscle, Smooth / metabolism
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Promoter Regions, Genetic
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / metabolism
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Pulmonary Fibrosis / pathology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Notch1 / genetics
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Receptor, Notch1 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Serrate-Jagged Proteins
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Transcription Factor HES-1
Substances
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Actins
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Antibiotics, Antineoplastic
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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Hes1 protein, mouse
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Homeodomain Proteins
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Intercellular Signaling Peptides and Proteins
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Jag1 protein, mouse
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Jagged-1 Protein
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Membrane Proteins
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Notch1 protein, mouse
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RNA, Messenger
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Receptor, Notch1
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Retnla protein, mouse
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Serrate-Jagged Proteins
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Transcription Factor HES-1
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Bleomycin
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Fucose
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Hydro-Lyases
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GDPmannose 4,6-dehydratase
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Hydroxyproline