Synergistic effects of dehydroepiandrosterone and retinoic acid on granulocytic differentiation of human promyelocytic NB4 cells

We report a novel effect of dehydroepiandrosterone (DHEA) on human granulocyte differentiation: DHEA enhances the all-trans-retinoic acid (ATRA)-induced differentiation of promyelocytic NB4 cells. DHEA (100 muM) significantly augmented the respiratory burst activity of NB4 cells treated with I nM ATRA, whereas DHEA alone did not induce respiratory burst activity. The protein and message expressions of p67(phox), the gene for the dose-limiting component of phagocyte NADPH oxidase, were significantly enhanced by the coexistence of DHEA and ATRA. The protein expression of P47(phox), another component of phagocyte NADPH oxidase, was also up-regulated by DHEA and ATRA. Moreover, the ATRA-induced increment of CCAAT/enhancer-binding protein beta (C/EBPbeta) and the reciprocal reduction in C/EBPalpha expression were also potentiated by DHEA. In contrast, the expression of PU. 1, a transcription factor reportedly involved in the basal expression of p67(phox), in monocytic cells, was only slightly up-regulated by DHEA and ATRA. Interestingly, DHEA sulfate (DHEAS), the sulfate ester of DHEA that exists in peripheral blood at a concentration approximately 3 orders of magnitude larger than that of DHEA, did not stimulate the ATRA-induced differentiation of NB4 cells. Thus, DHEA, but not DHEAS, plays important roles in synergy with ATRA during granulocyte differentiation of human promyelocytic NB4 cells. (C) 2005 The Japanese Society of Hematology.