Oncostatin M is a growth regulatory protein secreted by macrophages and activated T lymphocytes. In a hepatoma cell line (HepG2) the polypeptide very potently increased low density lipoprotein (LDL) uptake with an EC50 of 0.1-0.2 nM. The stimulation of LDL uptake was detectable by 2 h, was maximal by 8 h, and remained elevated through 20 h of oncostatin M incubation. In a similar fashion, oncostatin M also increased the number of cell surface LDL receptors by a mechanism that was inhibited by cycloheximide or the protein kinase C inhibitor H-7. Oncostatin M stimulation of LDL uptake and receptor protein occurred regardless of the state of cholesterol-dependent regulation of HepG2 LDL receptor (i.e. cells incubated in medium containing lipoproteins responded to the same extent as did cells incubated in the absence of lipoproteins). No significant effects were observed on sterol synthesis over 8 h or on DNA synthesis over 24 h. Oncostatin M induced rapid alterations in HepG2 phospholipid metabolism. Within 5-15 min there was a 20-50% increase in incorporation of 32P into several classes of phospholipids, including the phosphoinositides. Radiolabeled diacylglycerol levels were elevated 20% by 2 min and nearly 50% by 15 min. In addition, the polypeptide induced rapid increased (within 1 min) in phosphorylation of HepG proteins on tyrosine residues. Stimulation of both phosphotyrosine and LDL receptor up-regulation by oncostatin M was decreased by the tyrosine kinase inhibitor genistein. We propose that oncostatin M up-regulates HepG2 LDL receptor expression by a mechanism that includes stimulation of a tyrosine kinase followed by generation of phospholipid-related second messengers.