The role of RAR and RXR activation in retinoid-induced tissue factor suppression

Excessive expression of tissue factor (TF) is a common finding in leukaemic cells and may contribute to thrombotic complications in patients. Retinoic acid has been shown to induce differentiation and reduce TF expression in acute promyelocytic leukaemia (APL) cells in vitro, and to induce remission in APL patients. Treatment of the APL cell line N84 with the specific retinoic acid receptor-alpha (RAR alpha) agonists Ro40-6055 or TTNPB resulted in down-regulation of TF expression and in induction of differentiation. The activation of RAR beta, RAR gamma or retinoid chi receptor (RXR) did not suppress the constitutive TF expression in N84 cells. Moreover, the RAR alpha antagonist Ro41-5253 blocked the retinoid-induced down-regulation of TF. In contrast, in the monoblastic U-937 cell line only a partial suppression of TF antigen expression and activity was observed by treatment with the RAR agonist TTNPB or the RXR agonist SR11237 alone. However, the combination of TTNPB and SR11237 resulted in a pronounced down-regulation of TF expression and induction of differentiation in U-937 cells. We show for the first time that the activation of both subunits of the RAR alpha-RXR transcriptional complex is needed for TF suppression in U-939 cells, whereas in NB4 cells RAR alpha activation alone is sufficient. Thus, distinct molecular mechanisms for TF suppression seem to be operating In leukaemic cell lines of different origin.