Effects of dexamethasone on induction of monocytic differentiation in human U‐937 cells by dimethylsulfoxide

Abstract

The present studies demonstrate that dimethylsulfoxide (DMSO) treatment of human U-937 myelomonocytic leukemia cells is associated with induction of monocytic differentiation. The DMSO-induced U-937 monocytic phenotype was associated with 1) growth inhibition, 2) loss of clonogenic survival, 3) increases in alpha-naphthyl acetate esterase (NSE) staining, and 4) increases in cell surface expression of the monocyte marker Mac-1. DMSO treatment of U-937 cells was also associated with down-regulation of c-myc and c-myb gene expression as well as with increases in tumor necrosis factor (TNF) mRNA levels. The results further demonstrate that induction of U-937 monocytic differentiation by DMSO is accompanied by increases in phospholipase A2 activity. Moreover, this stimulation of phospholipase A2 was sensitive to dexamethasone. We therefore studied the effects of dexamethasone on DMSO-induced differentiation of U-937 cells. Although dexamethasone had no effect on growth inhibition or loss of clonogenic survival by DMSO, this glucocorticoid blocked increases in NSE staining and cell surface Mac-1 expression. Dexamethasone also had no effect on the down-regulation of c-myc and c-myb expression but blocked the reappearance of c-myb transcripts after 6 hr of DMSO treatment. Finally, dexamethasone inhibited DMSO-induced increases in TNF gene expression. Taken together, the results demonstrate that dexamethasone inhibits multiple characteristics, including the stimulation of phospholipase A2 activity, associated with DMSO-induced monocytic differentiation of U-937 cells.

Expression of the early growth response 1 and 2 zinc finger genes during induction of monocytic differentiation.

“…The treatment of U-937 cells with TPA is associated with induction of monocytic differentiation (22). Moreover, recent studies have demonstrated that DMSO similarly induces these cells along the monocytic lineage (21). DMSO treatment also increased EGR-l gene expression (Fig.…”

“…Taken together, these results indicated that M-CSF regulates EGR-I gene expression in monocytes by both transcriptional and posttranscriptional mechanisms, whereas EGR-2 expression is regulated at least in part by a posttranscriptional mechanism in these cells. We have previously demonstrated that glucocorticoids inhibit induction of monocytic differentiation (20)(21)(22). Consequently, we treated TPA-induced U-937 cells with dexamethasone to determine the effects of this agent on EGR-l gene expression.…”

“…Previous studies have demonstrated that the c-jun, jun-B, and c-fos genes are activated during TPA-induced monocytic differentiation (7,(17)(18)(19)(20). Moreover, the finding that pretreatment with dexamethasone inhibits expression of these genes, as well as TPA-or dimethyl sulfoxide (DMSO)-induced monocytic differentiation, has implicated a role for Jun/ AP-l in this process (20)(21)(22). In contrast, little is known about the regulation of the EGR gene family in hematopoietic cell differentiation.…”

Internucleosomal DNA fragmentation during phorbol ester-induced monocytic differentiation and G0/G1 arrest.

“…In the present work, the kinetics of DNA cleavage were dependent on the concentration ofTPA used to induce differentiation. Although the activation of endonucleolytic cleavage may have been related to the use of TPA rather than to induction of monocytic differentiation, similar patterns of DNA fragmentation were obtained with DMSO, another agent that differentiates U-937 cells along the monocytic lineage (28).…”

“…9 A). Recent work has demonstrated that DMSO also induces monocytic differentiation of U-937 cells (28). Treatment of U-937 cells with this agent was similarly associated with internucleosomal fragmentation (Fig.…”