ONCOSTATIN-M ACTIVATES LOW-DENSITY-LIPOPROTEIN RECEPTOR GENE-TRANSCRIPTION IN STEROL-REPRESSED LIVER-CELLS

Oncostatin M (OM), a cytokine produced by macrophages and activated T cells, has been shown to be a potent inducer of liver low density lipo protein receptor (LDLR) activity by increasing LDL uptake and cell sur face LDLR number in HepG2 cells. To investigate whether OM regulates t he transcription of the LDLR gene and if the effect is independent of the sterol pathway, we examined the effects of OM on the promoter acti vity of the LDLR gene and the expression of LDLR mRNA. HepG2 cells wer e transfected with hybrid genes containing three different lengths of DNA fragments from the 5' flanking region of the LDLR gene that were f used to the coding region of the chloramphenicol acetyltransferase (CA T) gene. OM induced an approximately 3-fold increase in CAT activities in pLDLR-CAT vector-transfected cells that were incubated in lipoprot ein-depleted medium and a g-fold increase in CAT activities when the t ransfected cells were treated with sterols. OM stimulated similar incr eases in CAT activities in HepG2 cells transfected with pLDLR-CAT 234, pLDLR-CAT 1563, and pLDLR-CAT 6500, suggesting that the essential cis -acting element that mediates the OM effect is located within the 177 base pairs upstream of the transcription start site of the LDLR gene. Examination of the regulation of the endogenous LDLR mRNA expression b y OM gave results similar to those in transfected cells. OM increased the levers of mRNA of LDLR, regardless of the presence or absence of l ipoprotein and sterols. These data suggest that the up-regulation of t he LDLR by OM is at the transcriptional level through a nonsterol medi ated mechanism.