Abstract
BackgroundMonocytes and macrophages are key innate immune effector cells that produce cytokines and chemokines upon activation. We and others have shown that 17β-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 FindingsIn this study, we quantify expression of ERα and ERβ in human monocytes and macrophages. We also show for the first time that the N-terminal truncated ERα variant, ERα46, is expressed in both cell types. Promoter utilization studies reveal that transcription of ERα in both cell types occurs from upstream promoters E and F. Treatment with E2 induces ERα expression in macrophages but has no effect on ERβ levels in either cell type. During monocyte-to-macrophage differentiation, ERα 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 ERα expression levels parallel the ability of E2 to suppress CXCL8 production.Conclusions/SignificanceThis work demonstrates for the first time that human macrophages predominantly express the truncated ER variant ERαp46, which is estradiol-inducible. This is mediated through usage of the ERα 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 ERα expression and regulation in the ability of E2 to modulate innate immune responses.
Highlights
Monocytes are released from the bone marrow into circulation and extravasate into peripheral tissues, where they differentiate into macrophages [1]
Using quantitative Taqman PCR, we demonstrated that ERa mRNA was expressed at higher levels than ERb in both freshly isolated monocytes (M0) and macrophages that had been differentiated with GM-CSF for 7 days
Consistent with these findings, total ERa protein levels were significantly higher in macrophages, while ERb protein expression was greater in monocytes (Figure 1B–D)
Summary
Monocytes are released from the bone marrow into circulation and extravasate into peripheral tissues, where they differentiate into macrophages [1]. Activation of innate immunity is mediated through recognition of distinct molecules that are present on a broad diversity of microorganisms. These pathogen-associated molecule patterns (PAMPs) are recognized by Toll-like receptors (TLRs) that are expressed by monocytes and macrophages. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, binds to its receptor TLR-4 and activates signaling cascades that result in the elaboration of cytokines and chemokines [2]. Production of these factors is important for the recruitment of other inflammatory effector cells and the activation of adaptive immunity. Relatively little is known about the ability of E2 to regulate isoform expression of estrogen receptors (ERs) in these cells
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