Abstract
Particulate matter (PM) is thought to be responsible for respiratory health problems. Epithelial cells exposed to particles release pro-inflammatory cytokines leading to inflammation of airways. However, the signaling cascades triggered by particles are poorly understood. We demonstrate that PM with an aerodynamic diameter < 2.5 microm (PM2.5) or diesel exhaust particles upregulate the expression of amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), in human bronchial epithelial cells. AR secretion was blocked by an inhibitor of the EGFR tyrosine kinase (AG1478), or a selective mitogen-activated protein (MAP) kinase/extracellular regulated kinase (Erk) inhibitor (PD98059), but not by the p38 MAP kinase inhibitor (SB203580). Thus, AR secretion is mediated through the activation of the EGFR and Erk MAP kinase pathway. In addition, AR secretion was inhibited by the antioxidant N-acetyl cysteine, but not by a neutralizing anti-EGFR, suggesting an EGFR transactivation via oxidative stress. AR may be involved in cytokine secretion, as AR can induce granulocyte macrophage-colony-stimulating factor (GM-CSF) release and a neutralizing anti-EGFR reduces the particle-induced GM-CSF release. This study indicates that PM2.5 induces the expression and secretion of AR, an EGFR ligand contributing to GM-CSF release, which may reflect an important mechanism for sustaining the proinflammatory response.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Air Pollutants / chemistry
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Air Pollutants / pharmacology*
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Amphiregulin
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Bronchi / cytology*
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Bronchi / drug effects
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Bronchi / metabolism
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Cells, Cultured
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EGF Family of Proteins
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Enzyme Inhibitors / pharmacology
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Epithelial Cells / drug effects*
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Epithelial Cells / metabolism
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / drug effects
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ErbB Receptors / metabolism
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Flavonoids / pharmacology
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Gene Expression Regulation / drug effects
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Glycoproteins / drug effects*
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Glycoproteins / genetics
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Glycoproteins / metabolism*
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Humans
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Imidazoles / pharmacology
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / drug effects
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism
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Particle Size
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Pyridines / pharmacology
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Reactive Oxygen Species / metabolism
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Signal Transduction
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Vehicle Emissions / adverse effects
Substances
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AREG protein, human
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Air Pollutants
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Amphiregulin
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EGF Family of Proteins
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Enzyme Inhibitors
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Flavonoids
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Glycoproteins
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Imidazoles
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Intercellular Signaling Peptides and Proteins
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Pyridines
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Reactive Oxygen Species
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Vehicle Emissions
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Granulocyte-Macrophage Colony-Stimulating Factor
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ErbB Receptors
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one