INHIBITION OF EGR-1 AND NF-KAPPA-B GENE-EXPRESSION BY DEXAMETHASONE DURING PHORBOL ESTER-INDUCED HUMAN MONOCYTIC DIFFERENTIATION

The treatment of human myeloid leukemia cells (HL-60, U-937, THP-1) with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with growth arrest and appearance of a differentiated monocytic phenotype. While previous studies have reported that the glucocorticoid dexamethasone blocks phenotypic characteristics of monocytic differentiation, we demonstrated in the present work that dexamethasone delays the effects of TPA on the loss of U-937 cell proliferation. We also demonstrated that this glucocortocoid inhibits TPA-induced increases in expression of the EGR-1 early response gene. The results of nuclear run-on assays and half-life experiments indicated that this effect of dexamethasone is regulated at the post-transcriptional level. Similar studies were performed for the NF-kappaB gene. While TPA treatment was associated with transient increases in NF-kappaB mRNA levels, this induction was blocked by dexamethasone. In contrast, dexamethasone had no significant effect on the activation of pre-existing NF-kappaB protein as determined in DNA-binding assays. Taken together, these findings suggest that the activated glucocorticoid receptor inhibits signaling pathways which include expression of the EGR-1 and NF-kappaB genes and that such effects may contribute to a block in TPA-induced monocytic differentiation.