Macrophage proteinases including cathepsin B (CB) are implicated in the tissue injury of inflammatory lesions. We have previously shown that interferon-gamma (IFN-gamma) increases intracellular levels of the lysosomal proteinase, CB, in THP-1 cell primed with phorbol 12-myristate 13-acetate (PMA). We have now examined the role of protein kinase C (PKC) in this effect. Following activation with PMA, the intracellular CB activity was significantly increased in the presence of 500 U/ml IFN-gamma. With the addition of protein kinase C (PKC) inhibitors bisindolylmaleimide, staurosporine, H-7, or phloretin a reversal of the effect of IFN-gamma was noted whereas the addition of the cyclic nucleotide-dependent protein kinase inhibitors HA 1004, H-8, H-89, or cAMP-Dependent Protein Kinase (PKA) Inhibitor did not block the effect. Although diacylglycerol (DAG) did not replace PMA in the study. Diacylglycerol Kinase Inhibitor induced a more pronounced augmentation and PKC depletion inhibited the effect. This suggests that a PKC-dependent pathway is involved in the response of CB in PMA primed THP-1 cells to IFN-gamma.