Regulation of cathepsin B activity by modulators of arachidonic acid metabolism in human monocytes

Cathepsin B (CB), a lysosomal cysteine proteinase, is implicated in tumour invasion and metastasis. Although direct exposure of THP-1 cells to arachidonic acid did not stimulate the induction of CB activity, cells treated with arachidonic acid followed by interferon-gamma (IFN-gamma), as well as concurrently treated cultures with arachidonic acid and lipopolysaccharide (LPS) or phorbol ester (PMA) increased CB activity in a dose-dependent manner. LPS and IFN-gamma-induced increases in CB were down-regulated by dexamethasone, an inhibitor of phospholipase A(2) (PLA(2)). Whereas dibutyryl cAMP, which increases PLA(2) activity, caused elevations in CB in THP-1 cells; inhibition of protein kinase A by H-89, which reduces PLA(2) expression, blocked the effect of dibutyryl cAMP. On the other hand, indomethacin, an inhibitor of cyclooxygenase, and ketoconazole, an inhibitor of lipoxygenase, up-regulated CB activity dose-dependently, indicating that the balance among PLA(2), cyclooxygenase and lipoxygenase activities might regulate the levels of CB synthesis. These data suggest that arachidonic acid may be associated with part of the intracellular signal pathway in the induction of CB activity by LPS, PMA and IFN-gamma.