The structural basis for steroid modulation of DMSO-stimulated erythrodifferentiation

The modulatory effect of 47 steroids on the DMSO stimulation of hemoglobin production in murine erythroleukemia cells was determined. The steroids capable of optimal inhibition of the DMSO effect most severely were glucocorticoids. Three steroids-halcinonide, flumethasone pivalate and flucloronide-were found to be active inhibitors at concentrations even lower than those noted for dexamethasone. Several steroids were noted to be capable of blocking the dexamethasone inhibition. Of these anti-inhibitors, fluoxymesterone and 17α-hydroxyprogesterone were the most active. The inhibitory and anti-inhibitory steroids were found to be the same steroid agonists or antagonists noted in other systems which are known to bind to glucocorticoid receptors. Therefore, it is likely that the activity of these steroids in erythroleukemia cell differentiation is mediated by typical glucocorticoid receptors. It was also shown that steroids strongly inhibit the DMSO effect only when present during DMSO stimulation of globin mRNA levels. This was further evidence that steroids were not acting at the level of translation. Since the same glucocorticoids that inhibit erythroid maturation in the mouse cells studied here also induce mouse lymphocytolysis and granulocytic differentiation, it is suggested that glucocorticoids may play an overall regulatory role in vivo in the determination of the numbers of mature blood cells of different types functioning in the organism. This type of corticosteroid action may occur in addition to any steroidal effects at earlier stages in hematopoiesis.