MCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epithelium
| Autor: | S. Marina Casalino-Matsuda, Maria E. Monzon, Rosanna Forteza |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Adult
Pulmonary and Respiratory Medicine RHOA MAP Kinase Signaling System Receptors CCR2 Physiology Caveolin 1 Bronchi Respiratory Mucosa Mucin 5AC Caveolae Models Biological Pulmonary Disease Chronic Obstructive Young Adult Downregulation and upregulation Physiology (medical) medicine Humans RNA Messenger Receptor Cells Cultured Chemokine CCL2 biology Smoking Mucin Articles Cell Biology Middle Aged respiratory system Mucin-5B Epithelium Cell biology medicine.anatomical_structure Gene Knockdown Techniques Immunology biology.protein GTP-Binding Protein alpha Subunits Gq-G11 Respiratory epithelium Signal transduction rhoA GTP-Binding Protein Signal Transduction |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 300:L204-L215 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | Cigarette smoke represents a major risk factor for the development of chronic obstructive pulmonary disease (COPD), a respiratory condition associated with airflow obstruction, mucus hypersecretion, chronic inflammation, and upregulation of inflammatory mediators such as the monocyte chemotactic protein-1 (MCP-1). MCP-1 through its receptor CCR2 induces chemotaxis and activates44/42MAPK, a kinase known to play a key role in mucin regulation in bronchial epithelium. In the present study we used differentiated primary cultures of normal human bronchial epithelial (NHBE) cells to test whether MCP-1 through its receptor CCR2 induces mucin upregulation. We have provided evidence that NHBE cells release MCP-1 to the epithelial surface and express the CCR2B isoform of the receptor mainly at the apical pole. In addition, we found that MCP-1 has a novel function in airway epithelium, increasing the two major airway mucins MUC5AC and MUC5B, an effect mediated, at least in part, by a cascade of events initiated by interaction of its receptor CCR2B with Gqsubunits in caveolae, followed by PLCβ, PKC, and44/42MAPK activation. We also have shown that MCP-1 is able to induce its own expression using the same receptor but through a different pathway that involves RhoA GTPase. Furthermore, we found that a single exposure to MCP-1 is enough to induce MCP-1 secretion and sustained mucin upregulation up to 7 days after initial exposure, an effect mediated by CCR2B as confirmed using short hairpin RNA. These results agree with our data in smoker's airway epithelium, where CCR2B is present in MUC5AC- and MUC5B-expressing cells and augmented MCP-1 expression is associated with increased MUC5AC and MUC5B immunolabeling, suggesting that the mechanisms described in primary cell cultures in the present study are operative in vivo. Therefore, therapeutic approaches targeting MCP-1/CCR2B may be useful in preventing not only influx of inflammatory cells to the airways but also mucus hypersecretion and goblet cell hyperplasia. |
| Databáze: | OpenAIRE |
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