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(American Journal of Pathology. 1999;155:1075-1085.)
© 1999 American Society for Investigative Pathology

Regular Articles

Modulation of the Gene Network Connected to Interferon- in Liver Regeneration from Oval Cells

Hanne Cathrine Bisgaard^*, Sven Müller^*, Peter Nagy, Lene Juel Rasmussen^* and Snorri S. Thorgeirsson

From the Department of Life Sciences and Chemistry,^*
Roskilde University, Roskilde, Denmark; the First Institute of Pathology and Experimental Cancer Research,
Semmelweis Medical University, Budapest, Hungary; and the Laboratory of Experimental Carcinogenesis,
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Suppression subtractive hybridization was used to clone genes associated with proliferation of oval cells in rat liver regenerating after a 70% partial hepatectomy combined with the feeding of 2-acetylaminofluorene. A subset of the identified genes comprised interferon- receptor subunit (IFN-R), gp91phox, interleukin-1ß (IL-1ß), lymphocyte function-associated molecule-1 (LFA-1), eukaryotic initiation factor-2-associated 67-kd protein (eIF-2-associated 67-kd protein), and -fetoprotein, which constitute part of the cellular program modulated by IFN-. Therefore, expression analysis performed by Northern blotting and immunohistochemistry were extended to include IFN-, the IFN- receptor ß subunit (IFN-Rß), three secondary response genes induced by interaction of IFN- with IFN- receptor complexes, ie, IL-1ß-converting enzyme (ICE), intercellular adhesion molecule-1 (ICAM-1), and urokinase-type plasminogen activator receptor (uPAR), and a cytokine inducing IFN- expression, ie, interleukin-18 (IL-18). The Northern blot analysis showed that all examined genes were modulated when progenitor-like oval cells were activated and recruited for liver regeneration. Immunohistochemistry localized the subunits of the IFN- receptor complex, IFN-R and IFN-Rß, the secondary response genes uPAR and ICAM-1, the IFN--inducing factor IL-18, and ICE to the ductular structures of oval cells. In contrast, during liver regeneration after a 70% partial hepatectomy, only modulation of IL-1ß and ICE was observed. Our results, therefore, indicate that IFN--mediated events may be particularly important when cells in the bile ductules must respond to liver damage by production of ductular oval cells.

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