Expression pattern and regulation of heme oxygenase-1/heat shock protein 32 in human liver cells.

Abstract

Heme oxygenase-1 (HO-1) is a stress response protein that is highly inducible under various conditions, such as oxidative or heat stress. The present study investigated expression pattern and regulation of HO-1 in human liver. Expression pattern of HO-1 immunoreactive protein was studied in liver biopsies by immunohistochemistry, revealing constitutive expression in Kupffer cells but not in hepatocytes. HO-1 was, however, inducible in hepatocytes and vascular tissue under pathological conditions, e.g. associated with fatty degeneration or liver malignancies. Regulation of HO-1 gene expression was further studied by Northern blot analysis in HepG2 cells and freshly isolated peripheral blood mononuclear cells as model systems of parenchymal and nonparenchymal liver cell populations, respectively. HO-1 mRNA was inducible in HepG2 cells and mononuclear cells by various agents inducing oxidative stress. However, HO-1 gene expression was not inducible by heat shock. Pyrrolidine dithiocarbamate, an inhibitor of nuclear factor kappaB-dependent gene expression, dose dependently decreased HO-1 mRNA transcripts in human mononuclear cells subjected to oxidative stress while slightly increasing HO-1 gene expression in HepG2 cells. In contrast, HO-1 induction upon oxidative stress was attenuated in HepG2 cells by cycloheximide and dexamethasone. Although activator protein-1 has been reported as the predominant redox-sensitive transcription factor inducing HO-1 expression in murine macrophages, nuclear factor kappaB seems to play a significant role in human mononuclear cells. Our data are consistent with a role for activator protein-1 in HO-1 induction in human HepG2 hepatoma cells. These data suggest a differential regulation of HO-1 gene expression in parenchymal and non-parenchymal human liver cells and may provide a topographic basis for the understanding of the role of the heme oxygenase/carbon monoxide pathway in human liver disease.