β-Estradiol Suppresses T Cell-Mediated Delayed-Type Hypersensitivity through Suppression of Antigen-Presenting Cell Function and Th1 Induction

Abstract

Background: Although an immunomodulatory role for estrogens has long been demonstrated by experimental and clinical observations, the mechanism by which estrogens exert their effect on T cells has not been clearly defined. Methods: In this study we analyzed the effects of β-estradiol (E2), at its contraceptive dose, on the delayed-type hypersensitivity (DTH) to purified protein derivatives (PPD) and associated immune response in female mice. Results: E2 treatment decreased PPD-specific DTH response, which coincided with a decrease in the leukocytes numbers in the draining lymph nodes (DLN) and spleen compared with control mice. E2 treatment also suppressed the in vitro PPD-specific proliferative response of DLN and spleen cells from PPD-primed mice. The analysis of production and gene expression of cytokines by DLN cells demonstrated that E2 treatment suppressed IL-2 and IFN-γ production in response to PPD in vitro. In contrast, IL-4 and IL-10 gene expression by DLN cells of E2-treated mice, taken 24 h after in vivo restimulation of mice with PPD, was enhanced. Furthermore, we found that spleen APC from E2-treated mice failed to induce optimum proliferation of the PPD-primed T cells in response to PPD in vitro. The impaired APC function by E2 was not due to induction of suppressor cell activity because addition of the normal spleen APC to APC from E2-treated mice restored the proliferative response of the PPD-primed T cells in response to PPD. Conclusion: Our results suggest that the E2-mediated inhibition of DTH reaction is due to a combination of the down regulation of APC function and deviation of the immune response from Th1-type to Th2-type.

Endocrine disrupters – potential modulators of the immune system and allergic response

“…Authors speculated that these effects were mediated not only through ER, as it had been established earlier (74)(75)(76), but also via non-ER pathways. The above-mentioned data correspond with results showing that estradiol treatment of adult mice decreased leukocyte numbers in the draining lymph nodes from the injected limb during the DTH response (77).…”

Modulatory effects of estrogen in two murine models of experimental colitis

“…Innate immunity and macrophages have, therefore, been suggested to play a role (17). Estrogen has been reported to suppress T cell-dependent DTH and activation of inflammatory cells producing TNF-␣ and IFN-␥ (51)(52)(53)58). Our data suggest a downregulation of the Th1 response associated to DNB colitis as reflected by decreased IFN-␥ mRNA expression 14 days postcolitis in 17␤-estradiol-treated mice.…”

Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α

“…The existence of such a regulatory mechanism has been described in models of T cell-mediated delayedtype hypersensitivity, where estrogen has been found to suppress T-cell proliferation through targeting of antigen-presenting cells (51,52). Similarly, previous reports from our laboratory demonstrated that estrogen represses stromal cell-soluble M-CSF production through targeting of IL-1-and TNF-producing bone marrow cells, rather than through a direct effect on mature stromal cells (16,27).…”