Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts

Portal fibroblasts (PF) are fibrogenic liver cells distinct from hepatic stellate cells (HSC). Recent evidence suggests that PF may be important mediators of biliary fibrosis and cirrhosis. The cytokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 is upregulated in biliary fibrosis by bile duct e...

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Bibliographic Details
Published in:American journal of physiology: Gastrointestinal and liver physiology 2006-04, Vol.290 (4), p.G765-G771
Main Authors: Kruglov, Emma A, Nathanson, Rebecca A, Nguyen, Trong, Dranoff, Jonathan A
Format: Article
Language:English
Subjects:
Animals
Bile Ducts - secretion
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Cells, Cultured
Chemokine CCL2 - administration & dosage
Chemokine CCL2 - secretion
Dose-Response Relationship, Drug
Epithelium - secretion
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Liver - cytology
Liver - drug effects
Liver - metabolism
Male
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - drug effects
Myocytes, Smooth Muscle - metabolism
Rats
Rats, Sprague-Dawley
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Summary:Portal fibroblasts (PF) are fibrogenic liver cells distinct from hepatic stellate cells (HSC). Recent evidence suggests that PF may be important mediators of biliary fibrosis and cirrhosis. The cytokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 is upregulated in biliary fibrosis by bile duct epithelia (BDE) and induces functional responses in HSC. Thus we hypothesized that release of MCP-1 may mediate biliary fibrosis. We report that PF express functional receptors for MCP-1 that are distinct from the receptor CCR2. MCP-1 induces proliferation, increase and redistribution of alpha-smooth muscle (alpha-SMA) expression, loss of the ectonucleotidase NTPDase2, and upregulation of alpha(1)-procollagen production in PF. BDE secretions induce alpha-SMA levels in PF, and this is inhibited by MCP-1 blocking antibody. Together, these data suggest that BDE regulate PF proliferation and myofibroblastic transdifferentiation in a paracrine fashion via release of MCP-1.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00308.2005