EFFECT OF PROTEIN-KINASE MODULATORS ON THE REGULATION OF CATHEPSIN-B ACTIVITY IN THP-1 HUMAN MONOCYTIC LEUKEMIA-CELLS

Cathepsin B (CB), a lysosomal cysteine proteinase, is implicated in ca ncer metastasis and inflammatory tissue injury. We examined the effect s of the protein kinase agonists and inhibitors on the regulation of C B activity in THP-1 human monocytic cells by two macrophage activators , lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). CB elevat ion induced by LPS alone or LPS followed by IFN-gamma was blocked by p rotein kinase C (PKC) inhibitors staurosporine, H-7, phloretin and bis indolylmaleimide, and by cyclic nucleotide-dependent protein kinase in hibitors HA 1004, H-8, H-89 and cAMP-dependent protein kinase (PKA) in hibitor. The CB activity by LPS and IFN-gamma were augmented by diacyl glycerol kinase inhibitor. PKC activator, phorbol 12-myristate 13-acet ate (PMA) and PKA activator, dibutyryl cAMP could replace LPS in primi ng the cells for IFN-gamma stimulation but 8-bromo-cGMP did not. These findings suggest that the activation of PKC and PKA appears to be inv olved at least in part in the induction of CB activity in THP-1 cells.