Mechanism for normal splenic T lymphocyte functions in proestrus females after trauma: enhanced local synthesis of 17β-estradiol

Abstract

and resuscitation (TH) produces profound immunodepression and enhances susceptibility to sepsis in males but not in proestrus females, suggesting gender dimorphism in the immune responses. However, the mechanism responsible for the maintenance of immune functions in proestrus females after TH is unclear. Splenic T lymphocytes express receptors for estrogen (ER), contain enzymes involved in estrogen metabolism, and are the major source of cytokine production; the metabolism of 17␤-estradiol was assessed in the splenic T lymphocytes of proestrus and ovariectomized mice by using appropriate substrates after TH. Analysis for aromatase and 17␤-hydroxysteroid dehydrogenases indicated increased 17␤-estradiol synthesis and low conversion into estrone in T lymphocytes of proestrus but not of ovariectomized mice. The effect of 17␤-estradiol on T lymphocyte cytokine release was reliant on ER expressions. This was apparent in the differences of ER expression, especially that of ER-␤, and an association between increased 17␤-estradiol synthesis and sustained release of IL-2 and IL-6 in T lymphocytes of proestrus females after TH. Because 17␤-estradiol is able to regulate cytokine genes, and the splenic T lymphocyte cytokine releases is altered after TH, continued synthesis of 17␤-estradiol in proestrus females appears to be responsible for the maintenance of T lymphocyte cytokine release associated with the protection of immune functions after TH. inflammation; immune suppression; steroid synthesis; T lymphocytes; cytokines THE INFLUENCE OF GENDER on immune functions has been recognized for many years, and in general, women are known to develop enhanced humoral responses compared with men and are more prone to autoimmune diseases (9,12,20). Trauma-hemorrhage and resuscitation (TH) produce severe impairment of both immune and cardiovascular functions (51,56,57). Although depression of cellular immunity occurs very early following TH, the loss in immune functions persists for a prolonged period, which may lead to subsequent sepsis with high mortality rates (43, 56). The immune depression is pronounced in males and ovariectomized females (OVX) after TH compared with proestrus females (54, 55). Moreover, immune functions in males and OVX females can be restored by the administration of 17␤-estradiol (E2) after TH (16-18). Thus gender dimorphism is obvious in the loss of immune functions after TH, implicating a major role for sex steroid hormones (2, 4).Steroid hormones regulate immune functions in vivo, and the mechanisms involve not only the control of cytokine gene transcription by the classic steroid hormone-receptor complex but also the tissue-specific metabolism of sex steroids (11,21,24,29,33,36,47). Among the sex steroids, estrogen is demonstrated to protect immune functions after TH because proestrus females are not immunodepressed compared with male and OVX mice. Furthermore, the depressed immune functions in males and OVX females after TH can be normalized by parenteral E2 administration (16-18). The ovary is the prima...

Effects of estrogen receptor subtype-selective agonists on immune functions in ovariectomized mice

“…Both ERα and ERβ are detected in murine splenic T cells [8]. However, ERβ expression has been found markedly lower than ERα [8] or present only in some Tcell subsets [4], which may explain the difference between our findings and those of Harrington et al [46] in transfected HEC-1 cells.…”

“…ERs are classified into two distinct subtypes-ERα and ERβ [2]. Both subtypes have been detected in thymus [3][4][5][6], bone marrow [7] and spleen [5,8]. The wide distribution of ERα and ERβ in the immune system implies their specific roles in mediating the immunomodulatory actions of estrogens.…”

Sex differences and estrogen modulation of the cellular immune response after injury

“…Following trauma, the expression of ER-β was significantly different in OVX mice; specifically it was decreased in proestrus mice but increased in OVX mice. Therefore, down-regulation of ER-β may then change expression of cytokines by T cells in these mice [112]. Other studies have suggested a spatial difference in immune-regulation by the two receptors with respect to tissue.…”

Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells

“…36 Androgens may act on telomerase expression in hematopoietic tissue after conversion in peripheral tissues to metabolites, such as 17␤-estradiol and 5␣-dihydrotestosterone; leukocytes express aromatase (CYP19), the enzyme responsible for aromatization of the testosterone A ring by conversion to 17␤-estradiol ( Figure 3E). 23,24,37 Androgens increased low baseline telomerase activity in individuals carrying a loss-of-function TERT mutation to normal levels (Table 3). These results have direct implications for patients with aplastic anemia carrying telomerase complex mutations and in dyskeratosis congenita, potentially explaining the effectiveness of male hormones in these syndromes, as well as guiding what type of androgenic compounds (readily aromatized) or even estrogens may be even more effective in the future.…”