Estradiol Regulates Expression of Estrogen Receptor ERα46 in Human Macrophages

Background: Monocytes and macrophages are key innate immune effector cells that produce cytokines and chemokines upon activation. We and others have shown that 17 beta-estradiol (E2) has a direct role in the modulation of monocyte and macrophage immune function. However, relatively little is known about the ability of E2 to regulate isoform expression of estrogen receptors (ERs) in these cells. Methodology/Principal Findings: In this study, we quantify expression of ER alpha and ER beta in human monocytes and macrophages. We also show for the first time that the N-terminal truncated ER alpha variant, ER alpha 46, is expressed in both cell types. Promoter utilization studies reveal that transcription of ER alpha in both cell types occurs from upstream promoters E and F. Treatment with E2 induces ER alpha expression in macrophages but has no effect on ER beta levels in either cell type. During monocyte-to-macrophage differentiation, ER alpha is upregulated in a time-dependent manner. Previous studies by our group demonstrated that E2 treatment attenuates production of the chemokine CXCL8 in an ER-dependent manner. We now show that ER alpha expression levels parallel the ability of E2 to suppress CXCL8 production. Conclusions/Significance: This work demonstrates for the first time that human macrophages predominantly express the truncated ER variant ER alpha p46, which is estradiol-inducible. This is mediated through usage of the ER alpha F promoter. Alternative promoter usage may account for tissue and cell type-specific differences in estradiol-induced effects on gene expression. These studies signify the importance of ER alpha expression and regulation in the ability of E2 to modulate innate immune responses.