Tumor necrosis factor-α production by human hepatoma cell lines is resistant to drugs that are inhibitory to macrophages

Little is known about the potential of immunomodulatory agents to lower tumor necrosis factor-alpha (TNF-alpha) synthesis in tissues of nomnonocytic origin. We studied effects of diverse drugs on the formation of immunoreactive TNF-alpha in the human hepatoma cell lines HepG2 and Hep3B, in which TNF-alpha production was induced by treatment (3 h incubation periods) with interleukin-1 beta (IL-1 beta, 300 pg/ml) or phorbol myristate acetate (BMA, 100 nmol/l), TNF-alpha production in IL-1 beta-stimulated or PMA-stimulated hepatocyte cultures was not altered following the addition of dihydrocortisone (less than or equal to 1 mu g/ml), dibutyryl-cAMP (db-cAMP, less than or equal to 100 mu mol/l), adenosine (less than or equal to 1 mmol/l), thalidomide (less than or equal to 25 mu g/ml), or cyclosporine (less than or equal to 300 ng/ml), TNF-alpha production was inhibited by taurolidine (greater than or equal to 300 mu g/ml), but this inhibition was associated with reduced cell viability. Pentoxifylline (1 mg/ml) did not influence PMA-induced TNF-alpha production, but it augmented IL-1 beta-induced TNF-alpha production. Measurements of TNF-alpha mRNA by RT-PCR indicated that pentoxifylline exerted its effect posttranscriptionally. Additional studies with PMA-treated human whole blood cultures confirmed that pentoxifylline, db-cAMP, and adenosine reduced TNF-alpha production by leukocytes. These results provide first evidence to assume cell type-specific effects of immunomodulatory drugs on TFN-alpha synthesis, which may be relevant with respect to their clinical application.