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LIVER AND BILIARY TRACT

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

Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut

Submitted 6 July 2005 ; accepted in final form 6 November 2005

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 -smooth muscle (-SMA) expression, loss of the ectonucleotidase NTPDase2, and upregulation of ₁-procollagen production in PF. BDE secretions induce -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.

biliary cirrhosis; biliary fibrosis; monocyte chemoattractant protein-1

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