Novel Role for Amphiregulin in Protection from Liver Injury

Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor α, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases. Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor α, heparin-binding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases. Hepatocyte apoptosis is a common mechanism to many forms of liver disease. It has been recognized to contribute to the pathogenesis of alcoholic liver disease, viral hepatitis, cholestatic liver disease, and ischemia/reperfusion injury (1Rust C. Gores G.J. Am. J. Med. 2000; 108: 567-574Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 2Jaeschke H. Gores G.J. Cederbaum A.I. Hinson J.A. Pessayre D. Lemasters J.J. Toxicol. Sci. 2002; 65: 166-176Crossref PubMed Scopus (1080) Google Scholar, 3Natori S. Rust C. Stadheim L.M. Srinivasan A. Burgart L.J. Gores G.J. J. Hepatol. 2001; 34: 248-253Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). More recently hepatocyte apoptosis has been reported to occur in the liver of patients with nonalcoholic steatohepatitis, correlating with the severity of the disease (4Feldstein A.E. Canbay A. Angulo P. Taniai M. Burgart L.J. Lindor K.D. Gores G.J. Gastroenterology. 2003; 125: 437-443Abstract Full Text Full Text PDF PubMed Scopus (854) Google Scholar). The consequences of hepatocellular apoptosis may extend beyond the mere loss of functional liver mass, because moderate and persistent apoptosis may contribute to the development of liver inflammation and fibrosis (5Faouzi S. Burckhardt B.E. Hanson J.C. Campe C.B. Schrum L.W. Rippe R.A. Maher J.J. J. Biol. Chem. 2001; 276: 49077-49082Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 6Canbay A. Friedman S. Gores G.J. Hepatology. 2004; 39: 273-278Crossref PubMed Scopus (470) Google Scholar). Apoptosis can be triggered by the activation of two molecular pathways: an intrinsic mitochondrially mediated cascade and a death receptor pathway. In the liver, the death receptor pathway appears to be predominant and involves the activation of cytokine receptors such as Fas, tumor necrosis factor receptor-1 and tumor necrosis factor-related apoptosis-inducing ligand receptors-1 and -2 (1Rust C. Gores G.J. Am. J. Med. 2000; 108: 567-574Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 2Jaeschke H. Gores G.J. Cederbaum A.I. Hinson J.A. Pessayre D. Lemasters J.J. Toxicol. Sci. 2002; 65: 166-176Crossref PubMed Scopus (1080) Google Scholar, 6Canbay A. Friedman S. Gores G.J. Hepatology. 2004; 39: 273-278Crossref PubMed Scopus (470) Google Scholar). Upon activation by their respective ligands these receptors initiate intracellular signaling cascades that ultimately lead to the activation of death-inducing proteolytic enzymes (1Rust C. Gores G.J. Am. J. Med. 2000; 108: 567-574Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 2Jaeschke H. Gores G.J. Cederbaum A.I. Hinson J.A. Pessayre D. Lemasters J.J. Toxicol. Sci. 2002; 65: 166-176Crossref PubMed Scopus (1080) Google Scholar). Fas is abundantly expressed in the liver, and Fas-mediated apoptosis has been shown to significantly contribute to toxic or viral damage and acute liver failure (7Ogasawara J. Watanabe-Fukunaga R. Adachi M. Matsuzawa A. Kasugai T. Kitamura Y. Itoh N. Suda T. Nagata S. Nature. 1993; 364: 806-809Crossref PubMed Scopus (1815) Google Scholar, 8Galle P. Hofmann W.J. Walczak H. Schaller H. Otto G. Stremmel W. Krammer P.H. Runkel L. J. Exp. Med. 1995; 182: 1223-1230Crossref PubMed Scopus (678) Google Scholar, 9Kanzler S. Galle P. Semin. Cancer Biol. 2000; 10: 173-184Crossref PubMed Scopus (135) Google Scholar). Interestingly, hepatocyte apoptosis observed in cholestasis is initiated by the ligand-independent activation of Fas by hydrophobic bile salts (1Rust C. Gores G.J. Am. J. Med. 2000; 108: 567-574Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 10Faubion W. Guicciardi M. Miyosi H. J. Clin. Invest. 1999; 103: 137-145Crossref PubMed Scopus (471) Google Scholar). In addition, lack of Fas expression or RNA interference targeting of Fas results in significant protection from fulminant hepatitis (7Ogasawara J. Watanabe-Fukunaga R. Adachi M. Matsuzawa A. Kasugai T. Kitamura Y. Itoh N. Suda T. Nagata S. Nature. 1993; 364: 806-809Crossref PubMed Scopus (1815) Google Scholar, 11Song E. Lee S.K. Wang J. Ince N. Ouyang N. Min J. Chen J. Shankar P. Lieberman J. Nat. Med. 2003; 9: 347-351Crossref PubMed Scopus (1032) Google Scholar). Altogether these observations underscore the clinical relevance of the Fas pathway in liver disease. The identification of agents that reduce hepatocellular apoptosis is thus of special significance for the development of hepatoprotective therapeutics (12Eichhorst S.T. Krueger A. Müerköster S. Fas S.C. Golks A. Gruetzner U. Schubert L. Opelz C. Bilzer M. Gerbes A.L. Krammer P.H. Nat. Med. 2004; 10: 602-609Crossref PubMed Scopus (70) Google Scholar, 13Galun E. Axelrod J.H. Biochim. Biophys. Acta. 2002; 1592: 345-358Crossref PubMed Scopus (105) Google Scholar). Intensive research in this area has shown that cytokines such as interleukin-6 (IL-6), 1The abbreviations used are: IL-6, interleukin-6; ALT, alanine aminotransferase; AR, amphiregulin; AST, aspartate aminotransferase; BTC, betacellulin; EGF, epidermal growth factor; EPR, epiregulin; ERK, extracellular regulated kinase; HB-EGF, heparin-binding EGF-like growth factor; MEK1, extracellular regulated kinase kinase-1; JNK, Jun N-terminal kinase; PI3K, phosphatidylinositol 3-kinase; STAT3, signal transducer and activator of transcription 3; TGF, transforming growth factor, TUNEL, terminal deoxynucleotide transferase-mediated dUDP nick-end labeling. growth factors like hepatocyte growth factor, or the hepatocyte-derived insulin-like growth factor binding protein-1 hepatoprotective the of apoptosis induced by Fas W. R. G. R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, Nagata S. Y. T. Biophys. PubMed Scopus Google Scholar, H. D. Krueger A. D. Fas S.C. A. D. 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Hepatology. 2004; 39: PubMed Scopus Google mice activation of the kinase Fas In of these we were to the that lack of contribute to the of chronic liver damage that precondition mice against subsequent liver The of of liver damage such as and the expression of in to and activation that lack of may in the development of chronic liver the of a protective response in the liver of as the resistance to and Interestingly, this response to be mediated by of the of because their expression was induced in the liver of we that the of were significantly up-regulated in the liver of these and were induced Fas as in wild type The of expression in mice administration may be by the cell death resistance the of damage and the endogenous protective response mediated in by with this we observed that the of in the signaling of the hepatoprotective effects of R. J. Clin. Invest. 2003; PubMed Scopus Google Scholar, T. C. U. J. J. W. C. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google were in The activation of these protective may the response of such as Fas in mice Am. J. 2003; PubMed Scopus Google Scholar, Chen 2001; PubMed Scopus Google Scholar). at the we in the resistance of mice to hepatocellular damage observations the hypothesis by A. M. J. M. M. Hepatology. 2004; 39: PubMed Scopus Google that persistent liver injury may resistance to subsequent cell death. Altogether show that expression is and induced in of liver the administration of that may be of the primary response of this The response of to is of because the liver is to endogenous from the that the Am. J. 2002; Scopus Google Scholar). It is thus the that the liver has to noxious be of In this an of AR, as in knock-out may contribute to the development of the chronic liver damage observed in these Interestingly, the chronic liver injury that in mice protection sublethal liver damage, these to be at a Fas These with the hepatoprotective of in underscore the role of in the protection from liver In observations a hepatoprotective role of and that this factor may be of therapeutic for patients with liver disease. The of is