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J. Biol. Chem., Vol. 281, Issue 22, 15090-15098, June 2, 2006

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Halofuginone Induces Matrix Metalloproteinases in Rat Hepatic Stellate Cells via Activation of p38 and NFB^*

Yury Popov¹, Eleonora Patsenker², Michael Bauer, Edith Niedobitek, Anja Schulze-Krebs, and Detlef Schuppan³

From the Department of Medicine I, University of Erlangen-Nuernberg, 91054 Erlangen, Germany and the Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115

The semisynthetic plant alkaloid halofuginone (HAL) was reported to prevent and partly reverse experimental liver fibrosis. However, its mechanisms of action are poorly understood. We therefore aimed to determine the antifibrotic potential of HAL and to characterize involved signal transduction pathways in hepatic stellate cells (HSCs). Results were compared with its in vivo effects in a rat model of reversal of established liver fibrosis induced by thioacetamide. In vitro HAL inhibited HSC proliferation and migration dose dependently at submicromolar concentrations. HAL (200 nM) up-regulated matrix metalloproteinase (MMP)-3 and MMP-13 expression between 10- and 50-fold, resulting in a 2- to 3-fold increase of interstitial collagenase activity. Procollagen 1(I) and MMP-2 transcript levels were suppressed 2- to 3-fold, whereas expression of other profibrogenic mRNAs remained unaffected. p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor B(NFB) pathways were activated by HAL, and specific inhibitors of p38 MAPK and NFB dose dependently inhibited MMP-13 induction. Treatment with HAL did not affect HSC viability, and observed effects were reversible after its removal. In vivo HAL up-regulated MMP-3 and -13 mRNA expression 1.5- and 2-fold, respectively, in cirrhotic rats, whereas tissue inhibitor of metalloproteinase-1 was suppressed by 50%. In conclusion, submicromolar concentrations of HAL inhibit HSC proliferation and migration and up-regulate their expression of fibrolytic MMP-3 and -13 via activation of p38 MAPK and NFB. The remarkable induction of MMP-3 and -13 makes HAL a promising agent for antifibrotic combination therapies.

Received for publication, January 3, 2006

^* This work was supported in part by the Deutsche Forschungsgemeinschaft (DFG, Grant 646/14-1), by the German Competence Network for Viral Hepatitis, and by the Interdisciplinary Center for Clinical Research of the University of Erlangen-Nuernberg (to D. 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.

¹ Recipient of Yamanouchi (2002) and Sheila Sherlock (2003) Fellowships of the European Association for the Study of the Liver.

² Recipient of a scholarship of the DFG graduate college (GRK 750).

³ To whom correspondence should be addressed: Division of Gastroenterology and Hepatology, Beth Israel Deaconess MC, Harvard Medical School, Dana 501, 330 Brookline Ave, Boston, MA 02215. Tel.: 617-667-8377; Fax: 617-667-2767; E-mail: dschuppa{at}bidmc.harvard.edu.

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