MCP-1/CCR2B-dependent loop upregulates MUC5AC and MUC5B in human airway epithelium

Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L204-15. doi: 10.1152/ajplung.00292.2010. Epub 2010 Nov 19.

Abstract

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 activates (44/42)MAPK, 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 G(q) subunits in caveolae, followed by PLCβ, PKC, and (44/42)MAPK 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bronchi / drug effects
  • Bronchi / metabolism
  • Caveolae / metabolism
  • Caveolin 1 / metabolism
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism*
  • Chemokine CCL2 / pharmacology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Gene Knockdown Techniques
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Middle Aged
  • Models, Biological
  • Mucin 5AC / metabolism*
  • Mucin-5B / metabolism*
  • Pulmonary Disease, Chronic Obstructive / etiology
  • Pulmonary Disease, Chronic Obstructive / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*
  • Signal Transduction / drug effects
  • Smoking / adverse effects
  • Smoking / metabolism
  • Young Adult
  • rhoA GTP-Binding Protein / metabolism

Substances

  • CAV1 protein, human
  • CCL2 protein, human
  • Caveolin 1
  • Chemokine CCL2
  • MUC5AC protein, human
  • MUC5B protein, human
  • Mucin 5AC
  • Mucin-5B
  • RNA, Messenger
  • Receptors, CCR2
  • RHOA protein, human
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • rhoA GTP-Binding Protein