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J. Biol. Chem., Vol. 280, Issue 24, 22986-22992, June 17, 2005

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Portal Fibroblasts Regulate the Proliferation of Bile Duct Epithelia via Expression of NTPDase2^*

M. Nauman Jhandier, Emma A. Kruglov, Élise G. Lavoie, Jean Sévigny, and Jonathan A. Dranoff¶

From the Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06520 and the Centre de Recherche en Rheumatologie et Immunologie, Université Laval, Sainte-Foy, Quebec G1K 7P4, Canada

Bile duct epithelia are the target of a number of "cholangiopathies" characterized by disordered bile ductular proliferation. Although mechanisms for bile ductular proliferation are unknown, recent evidence suggests that extracellular nucleotides regulate cell proliferation via activation of P2Y receptors. Portal fibroblasts may regulate bile duct epithelial P2Y receptors via expression of the ecto-nucleotidase NTPDase2. Thus, we tested the hypothesis that portal fibroblasts regulate bile duct epithelial proliferation via expression of NTPDase2. We generated a novel co-culture model of Mz-ChA-1 human cholangiocarcinoma cells and primary portal fibroblasts. Cell proliferation was measured by bromodeoxyuridine uptake. NTPDase2 expression was assessed by immunofluorescence and quantitative real-time reverse transcription PCR. NTPDase2 expression in portal fibroblasts was blocked using short interfering RNA. NTPDase2 overexpression in portal myofibroblasts isolated from bile duct-ligated rats was achieved by cDNA transfection. Co-culture of Mz-ChA-1 cells with portal fibroblasts decreased their proliferation to 26% of control. Similar decreases in Mz-ChA-1 proliferation were induced by the soluble ecto-nucleotidase apyrase and the P2 receptor inhibitor suramin. The proliferation of Mz-ChA-1 cells returned to baseline when NTPDase2 expression in portal fibroblasts was inhibited using NTPDase2-specific short interfering RNA. Untransfected portal myofibroblasts lacking NTPDase2 had no effect on Mz-ChA-1 proliferation, yet portal myofibroblasts transfected with NTPDase2 cDNA inhibited Mz-ChA-1 proliferation. We conclude that portal fibroblasts inhibit bile ductular proliferation via expression of NTPDase2 and blockade of P2Y activation. Loss of NTPDase2 may mediate the bile ductular proliferation typical of obstructive cholestasis. This novel cross-talk signaling pathway may mediate pathologic alterations in bile ductular proliferation in other cholangiopathic conditions.

Received for publication, November 2, 2004 , and in revised form, March 25, 2005.

^* This work was supported by National Institutes of Health Grants DK02379 (to J. A. D.) and DK066287 (to the Yale Liver Center), the Robert Leet and Clara Patterson Trust (to J. A. D.), the American Association for the Study of Liver Diseases (to J. A. D.), and the Canadian Institutes of Health Research (MOP-49460) (to J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar St. LMP 1080, New Haven, CT 06520. Tel.: 203-785-4133; Fax: 203-785-7273; E-mail: jonathan.dranoff{at}yale.edu.

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