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 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.
Kruglov
Emma A
EA
Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Nathanson
Rebecca A
RA
Nguyen
Trong
T
Dranoff
Jonathan A
JA
D000818:Animals; D001652:Bile Ducts / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000008:administration & dosage* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2