Induction of granulocytic differentiation in myeloblasts by 17-beta-estradiol involves the leukotriene D4 receptor.

17-beta-Estradiol (beta E) causes granulocytic differentiation and neutrophilia in mice. However, the presence of estrogen receptors in myeloblasts and granulocytic progenitor cells has not been reported. beta E can be converted to a bioreactive species, estradiolquinone. We have previously shown that hydroquinone (HQ), via conversion to bioreactive p-benzoquinone (BQ), causes neutrophilia in mice and induces granulocytic differentiation in myeloblasts through interaction with the leukotriene D4 (LTD4) receptor. Therefore, we tested whether beta E could be oxidized by a myeloperoxidase-mediated reaction to a bioreactive intermediate, which might, in turn, induce granulocytic differentiation in mouse myeloblasts by activating the LTD4 receptor, thus obviating the need for LTD4, the downstream intracellular mediator of granulocyte colony-stimulating factor (G-CSF)-induced signal transduction. The interleukin (IL)-3-dependent, G-CSF-inducible normal mouse myeloblastic cell line, 32D cl 3(G), was used to determine the ability of beta E to induce terminal granulocytic differentiation in myeloblasts. Morphological analysis of stage-specific granulocytic differentiation indicated that beta E was capable of the concentration- (10(-8)-10(-4)M) and time-(6d) dependent induction of a complete program of terminal granulocytic differentiation in myeloblasts similar to that seen with G-CSF or LTD4. beta E-induced granulocytic differentiation was prevented by the peroxidase inhibitor, indomethacin, and was completely and competitively inhibited in the presence of a specific LTD4 receptor antagonist, MK-571, suggesting that a bioreactive form of estradiol, such as estradiolquinone, is interacting with the receptor. beta E was shown to cause a similar concentration-dependent induction of granulocytic differentiation in human HL-60 myeloblasts that was also inhibited by the receptor antagonist. Biological effects of beta E in nontarget tissues may result from the interaction of bioreactive estradiolquinone with critical cellular macromolecules involved in normal cellular signaling pathways.