Modulation of transglutaminase activity in mononuclear phagocytes and macrophage-like tumor cell lines by differentiation agents.

The effect of glucocorticosteroids, retinoids, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the tumor promoter phorbol myristate acetate (TPA) on the expression of transglutaminase activity in vitro differentiating bone marrow-derived mouse and rat mononuclear phagocytes (BMDMP) and mouse and human myeloid leukemia cell lines was assessed. Dexamethasone was found to induce an increase of about 100% in transglutaminase activity in mouse and rat BMDMP. The effect was time- and dose-dependent, and specific for steroids with glucocorticoid activity. Retinoic acid (RA) suppressed transglutaminase activity in mouse BMDMP (approximately 50%) and enhanced it in rat BMDMP (100-200%). Other retinoids were less effective. 1,25(OH)2D3 had little effect on transglutaminase expression in mouse BMDMP and suppressed it in rat BMDMP (approximately 60%). TPA exerted a suppressive effect (approximately 50%) on transglutaminase activity of both rat and mouse BMDMP. In murine (P388D1 and J774.2) and human (ML3, HL-60, KG-1, HEL, U937) myeloid leukemia cell lines, dexamethasone enhanced transglutaminase activity to a varying degree (100-1,000%), RA suppressed it in P388D1 cells (approximately 70%) and enhanced it in the other cell lines (100-1,500%), 1,25(OH)2D3 induced a rather small augmentation of enzyme expression, whereas TPA suppressed enzyme expression (70-100%). The species-specific differences previously observed by us for the effect of RA, dexamethasone and 1,25(OH)2D3 on the formation of BMDMP from mouse and rat bone marrow progenitor cells are now shown to extend also to effects on expression of transglutaminase activity. From a mechanistic point of view it is of interest that dexamethasone uniformly enhanced transglutaminase activity, whereas TPA suppressed it. RA and 1,25(OH)2D3 induced either suppression or enhancement in the various cell types, with no correlation between the direction of the effect of the two agents. The data suggest that modulation of transglutaminase activity by the four agents occurs via disparate mechanisms.