Role of Estrogen Receptor   in Hematopoietic Stem Cell Development and B Lymphocyte Maturation in the Male Mouse

Abstract

Although estrogens and estrogen receptors (ERs) are known to function in the male brain and reproductive tract, few studies have evaluated their involvement in the male hematopoietic and immune systems. This study was undertaken to determine the role of ERalpha in hematopoietic progenitor and B lymphocyte maturation. ERalpha knockout (ER-/-), wild-type (ER+/+), and radiation chimeric (ERalpha positive or negative in either nonhematopoietic or hematopoietic elements, or both) male mice were used to determine target tissues. ER-/- and ER+/+ animals showed similar hematopoietic progenitor profiles, but the ER-/- animals had fewer cells in all bone marrow B lymphocyte subpopulations. Animals receiving a pharmacological dose (5 mg/kg BW) of 17beta-estradiol (E2) with both elements, ER+/+, had decreased early hematopoietic progenitors and a shift toward a mature B cell subpopulation, whereas animals with both elements, ER-/-, showed changes only in early hematopoietic progenitors. Hematopoietic element ER+/+ animals exhibited greater E2-induced hematopoietic progenitor and B lymphocyte alterations than those having only nonhematopoietic ERalpha. These data indicate that 1) ERalpha is not necessary for regulating male mouse normal hematopoietic progenitor cell proportions, but is involved in B cell regulation; and 2) ERalpha in hematopoietic elements is predominantly responsible for mediating E2-induced hematopoietic and B cell changes.

Local cytokine levels associated with delayed-type hypersensitivity responses: modulation by gender, ovariectomy, and estrogen replacement

“…Interpretation of changes in DTH responses in these mice, however, would be complex since estrogen receptor knockout mice have been shown to have altered immune development as well as function (Staples et al 1999, Thurmond et al 2000. No known studies on the immunity of androgen knockout mice have been published so far, but one might expect similar complications to interpretation.…”

Sex Steroids and Stem Cell Function

“…17β-estradiol treatment reduces cμ+ pre-B cells, associated with a decrease in Ig gene rearrangements and rag1 transcripts (62). It also has been demonstrated that ERα is predominantly responsible for mediating 17β-estradiol induced changes in B-cell precursors (63,64). These findings suggest that 17β-estradiol exerts negative influence on the production of B-lineage cells by modifying the differentiation, proliferation, and survival of early B-cell precursors.…”

Neuro-endocrine-immune Crosstalk and Implications for Cancer Therapy

“…While some studies indicate that ERβ is the main negative regulator of hematopoietic progenitor cells [60,64], others suggest that this effect can be mediated through either ERα or ERβ [58,65]. The decreased lymphopoiesis may reflect an intrinsic B-cell response to estrogen of early lymphoid progenitors [62,66] and/ or indirect estrogen-dependent regulation of production and secretion of cytokines, such as IL-7, required for the development of early B lymphopoietic stages [58,66]. Furthermore, engagement of ERα, seems to be a trigger for autoimmunity and leads to breakdown in B-cell tolerance, with increased survival to immunocompetence of high-affinity autoreactive B lymphocytes.…”

“…For instance, gender has been shown to be an important and independent predictor of clinical outcome and survival in cutaneous melanoma, with premenopausal females (but not women older than 60 years) experiencing an improved prognosis [72,73]. The presence of sex steroid receptors in hematopoietic elements [24,58,66], as well as thymic and BM stromal cells [74][75][76] suggests that they may have a direct or indirect effect on immunity and hematopoiesis. The sexual dimorphism of the immune response could be modulated by differences in T cell receptor signaling, expression of activation molecules on T lymphocytes and antigenpresenting cells [77], transcription or translation of cytokine genes, or lymphocyte homing [20].…”