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

Abstract

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-gamma receptor alpha subunit (IFN-gammaRalpha), gp91phox, interleukin-1beta (IL-1beta), lymphocyte function-associated molecule-1alpha (LFA-1), eukaryotic initiation factor-2-associated 67-kd protein (eIF-2-associated 67-kd protein), and alpha-fetoprotein, which constitute part of the cellular program modulated by IFN-gamma. Therefore, expression analysis performed by Northern blotting and immunohistochemistry were extended to include IFN-gamma, the IFN-gamma receptor beta subunit (IFN-gammaRbeta), three secondary response genes induced by interaction of IFN-gamma with IFN-gamma receptor complexes, ie, IL-1beta-converting enzyme (ICE), intercellular adhesion molecule-1 (ICAM-1), and urokinase-type plasminogen activator receptor (uPAR), and a cytokine inducing IFN-gamma 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-gamma receptor complex, IFN-gammaRalpha and IFN-gammaRbeta, 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 hepatectomy, only modulation of IL-1beta and ICE was observed. Our results, therefore, 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.

Differential lymphotoxin‐β and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury†

“…It is also possible that these cytokines are involved in paracrine signaling of oval cells, because we demonstrate that all three transcripts are abundant in purified oval cells, and it has been shown by Bisgaard et al 15 that IFN␥ receptor subunits are expressed by oval cell ductular structures after their induction by 2-acetylaminofluorene coupled with PHx.…”

“…Subtractive hybridization comparing transcripts from nonparenchymal cells after 2-acetylaminofluorene coupled with PHx and PHx-identified genes induce IFN␥, IFN␥ receptor subunits 1 and 2, primary and secondary response genes, and IFN␥-induced cell adhesion molecules. 15 Using a liver progenitor cell line, PIL-2, 28 we showed IFN␥ rapidly induces STAT-3 phosphorylation when it is added to cultures. This result suggests a direct effect of IFN␥ in activating this signaling pathway that, in several in vitro studies, is shown to link cytokine signaling with cell proliferation.…”

“…12, 13 We previously showed that TNF␣ signaling is necessary for an optimal oval cell-mediated regenerative response to a CDE diet, 14 whereas IFN␥ signaling has been implicated in the oval cell-mediated regenerative response to 2-acetylaminofluorene coupled with PHx in the rat. 15 Thus, TNF␣ plays a positive role in both hepatocytemediated and oval cell-mediated liver regeneration; and although IFN␥ inhibits hepatocyte-mediated regeneration, its effect on oval cells is unknown.…”

Thy-1 Is Expressed in Hepatic Myofibroblasts and Not Oval Cells in Stem Cell-Mediated Liver Regeneration

“…14 The cDNA for rat Thy-1 encompassed nucleotides 46 to 531 (GenBank accession no. NM_012673), and for ␣-fetoprotein (AFP), nucleotides 101 to 329 (GenBank accession no.…”

Oval cell‐mediated liver regeneration: Role of cytokines and growth factors

“…48 Suppression subtractive hybridization following 2-AAF/PH identified genes associated with the proliferation of oval cells including IFN-g, IFN-g receptor a subunit (IFN-gRa), IFN-gRb primary response genes (gp91phox), IFN-gRb secondary response genes such as ICE, CD54/ICAM-1 and uPAR, cytokines that induce expression of IFN-g, which include IL1-b and IL-18, and cell adhesion molecules that regulate the interactions between lymphocytes and epithelial cells; lymphocyte functionassociated molecule 1-a (LFA-1a/CD11 and CD54/ ICAM-1). These proteins are all part of the complex cellular response associated with the IFN-g signaling cascade.…”