Modulation of the gene network connected to interferon-gamma in liver regeneration from oval cells

Suppression subtractive hybridization was used to clone genes associated wi th proliferation of oval cells in rat liver regenerating after a 70% partia l hepatectomy combined with the feeding of 2-acetylaminofluorene, A subset of the identified genes comprised interferon-gamma receptor alpha subunit ( IFN-gamma R alpha), gp91phox, interleukin-1 beta (IL-1 beta), lymphocyte fu nction-associated molecule-1 alpha (LFA-1), eukaryotic initiation factor-2- associated 67-kd protein (eIF-2-associated 67-kd protein), and alpha-fetopr otein, which constitute part of the cellular program modulated by IFN-gamma , Therefore, expression analysis performed by Northern blotting and immunoh istochemistry were extended to include IFN-gamma, the IFN-gamma receptor be ta subunit (IFN-gamma R beta), three secondary response genes induced by in teraction of IFN-gamma with IFN-gamma receptor complexes, ie, IL-1 beta-con verting enzyme (ICE), intercellular adhesion molecule-1 (ICAM-1), and uroki nase-type plasminogen activator receptor (uPAR), and a cytokine inducing IF N-gamma expression, ie, interleukin-18 (IL-18). The Northern blot analysis showed that all examined genes were modulated when progenitor-like oval cel ls were activated and recruited for liver regeneration. Immunohistochemistr y localized the subunits of the IFN-gamma receptor complex, IFN-gamma R alp ha and IFN-gamma R beta, the secondary response genes uPAR and ICAM-1, the IFN-gamma-inducing factor IL-18, and ICE to the ductular structures of oval cells. In contrast, during liver regeneration after a 70% partial hepatect omy, only modulation of IL-1 beta and ICE was observed. Our results, theref ore, indicate that IFN-gamma-mediated events may be particularly important when cells in the bile ductules must respond to liver damage by production of ductular oval cells.