Synergism and antagonism in the effects of 1 alpha,25-dihydroxyvitamin D3, retinoic acid, dexamethasone, and a tumor-promoting phorbol ester on the functional capability of P388D1 cells: phagocytosis and transglutaminase activity.

1 alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] and retinoic acid (RA) induce a high-phagocytic phenotype in the macrophage-like tumor cell line P388D1. A concurrent cultivation of P388D1 cells in the presence of suboptimal concentrations of both agents led to an extent of induction of phagocytic activity that surpassed the additive effect of either of the agents alone; i.e., 1,25(OH)2D3 and RA synergistically induce the phagocytic capability of P388D1 cells. Dexamethasone and 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (TPA) did not induce a high-phagocytic phenotype in P388D1 cells and affected differentially the high-phagocytic phenotype induced by RA and 1,25(OH)2D3. Dexamethasone inhibited the phagocytic activity induced by RA (80% at 24 h), while it had small suppressive effects on that induced by 1,25(OH)2D3. TPA suppressed the phagocytic activity induced by RA (60% within 96 h) while potentiating the expression of the high-phagocytic phenotype induced by 1,25(OH)2D3 (50% increase with 96 h). The observed effects did not involve modulation of prostaglandin synthesis or intracellular cyclic adenosine 3':5'-monophosphate. Expression of transglutaminase activity in P388D1 cells was also modulated differentially by the four agents; 1,25(OH)2D3 treatment had no effect on enzyme level, RA and TPA suppressed it, and dexamethasone increased it. The data suggest that: 1,25(OH)2D3 and RA act via disparate mechanisms that can operate simultaneously; the elements induced in P388D1 cells by 1,25(OH)2D3 and RA, and which are responsible for the phagocytic activity, differ in their sensitivity to dexamethasone and TPA; and transglutaminase activity in P388D1 cells is readily manipulable, but there seems to be no straightforward correlation between the level of its activity and the phagocytic capability of the cells or their rate of proliferation.