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.

Carlsten H, Holmdahl R, Tarkowski A, Nilsson LA: Oestradiol suppression of delayed type hypersensitivity in autoimmune (NZB/NZW)F1 mice is a trait inherited from the healthy NZW parental strain. Immunology 1989;67:205–209.
Carlsten H, Holmdahl R, Tarkowski A: Analysis of the genetic encoding of oestradiol suppression of delayed-type hypersensitivity in (NZB × NZW) F1 mice. Immunology 1991;73:186–190.
Carlsten H, Verdrengh M, Taube M: Additive effects of suboptimal doses of estrogen and cortison on the suppression of T lymphocyte dependent inflammatory responses in mice. Inflamm Res 1996;45:26–30.
Luster MI, Boorman GA, Dean JH, Luebke RW, Lawson LD: The effect of adult exposure to diethylstilbestrol in the mouse: Alterations in immunological functions. J Reticuloendothel Soc 1980;28:561–569.
Holmdahl R, Jansson L, Meyerson B, Klareskog L: Oestrogen induced suppression of collagen arthritis. I. Long-term oestradiol treatment of DBA/1 mice reduces severity and incidence of arthritis and decreases the anti type II collagen immune response. Clin Exp Immunol 1988;70:372–378.
Kato K, Chen Y, Nakane A, Minagawa T, Fujieda K, Kimura T, Yamamoto K: Suppression of delayed-type hypersensitivity in mice pretreated with diethylstilbestrol: Involvement of sex hormones in immunomodulation. J Leukoc Biol 1988;43:530–538.
Hoek A, von Kasteren Y, de Haan-Meulman M, Hooijkaas H, Schoemaker J, Drexhage A: Analysis of peripheral blood lymphocyte subsets, NK cells, and delayed type hypersensitivity skin test in patients with premature ovarian failure. Am J Reprod Immunol 1995;33:495–502.
Gulshan S, McCruden U, Stimson W: Oestrogen receptors in macrophages. Scand J Immunol 1990;31:691–697.
Cohen JH, Danel L, Cordier G, Saez S, Revillard J: Sex steroid receptors in peripheral T cells: Absence of androgen receptors and restriction of estrogen receptors to OKT8-positive cells. J Immunol 1983;131:2767–2771.
Suenaga R, Evans M, Mitamura K, Rider V, Abdou N: Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells. J Rheumatol 1998;25:1305–1312.
Benten WP, Lieberherr M, Giese G, Wunderlich C: Estradiol binding to cell surface raises cytosolic free calcium in T cells. FEBS Lett 1998;422:349–353.
Dean JH, Laver LD, Murray MJ, Luster MI, Neptun D, Adams D: Functions of mononuclear phagocytes in mice exposed to diethylstilbestrol: A model of aberrant macrophage development. Cell Immunol 1986;102:315–322.
Schreiber AD, Nettl FM, Sanders MC, King M, Szabolcs P, Freidman D, Gomez F: Effect of endogenous and synthetic sex steroids on the clearance of antibody-coated cells. J Immunol 1988;141:2959–2966.
Stimson PJ, Crilly OJ: Effects of steroids on the secretion of immunoregulatory factors by thymic epithelial cell cultures. Immunology 1981;44:401–407.
Yu L, Ma R, Yu T: Antitumor and antitumor-promoting actions of macrophages and their relationship with estrogen. Oncology 1996;53:322–326.
Frazier-Jessen MR, Mott FJ, Whitte PI, Kovacs EJ: Estrogen suppression of connective tissue deposition in a murine of peritoneal adhesion formation. J Immunol 1996;156:3036–3042.
Ansar Ahmed A, Dauphinee M, Talal N: Effects of short-term administration of sex hormones on normal and autoimmune mice. J Immunol 1985;134:204–210.
Ansar Ahmed A, Talal N: Sex hormones and the immune system. Part 2. Animal data. Baillière’s Clin Rheumatol 1990;41:13–31.
Cutolo M, Sulli A, Seriolo B, Accardo S, Masi AT: Estrogens, the immune response and autoimmunity. Clin Exp Rheumatol 1995;13:217–226.
Gilmore W, Weiner LP, Correale J: Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects. J Immunol 1997;158:446–451.
Rijhsinghani A, Thompson K, Bhatia S, Waldschmidt T: Estrogen blocks early T cell development in the thymus. Am J Reprod Immunol 1996;36:269–277.
Henriksen O, Frey JR: Control of the expression of interleukin-2 activity. Cell Immunol 1982;73:106–114.
Pung OJ, Tucker AN, Vore SJ, Luster MI: Influence of estrogen on host resistance: Increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin 2. Infect Immun 1985;50:91–96.
Salem ML, Matsuzaki G, Madkour GM, Nomoto K: β-Estradiol-induced decrease in IL-12 and TNF-α expression suppresses macrophage functions in the course of Listeria monocytogenes infection in mice. Int J Immunopharmacol 1999;21:481–497.
Fox HS, Bond BL, Parslow TG: Estrogen regulates the IFN-γ promoter. J Immunol 1991;146:4362–4367.
Prabhala R, Wira C: Sex hormone and IL-6 regulation of antigen presentation in the female reproductive tract mucosal tissues. J Immunol 1995;155:5566–5573.
Wira R, Rossoll R: Antigen-presenting cells in the female reproductive tract: Influence of sex hormones on antigen presentation in the vagina. Immunology 1995;84:505–508.
Weinstein Y, Ran S, Segal S: Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse. J Immunol 1984;132:656–661.
Keisler LW, Walker SE: Suppression of reproductive function in autoimmune NZB/W mice: Effective doses of four contraceptive steroids. Am J Reprod Immunol 1987;14:115–121.
Keisler LW, Kier AB, Walker SE: Effects of prolonged administration of the 19-nor-testosterone derivatives norethindrone and norgestrel to female NZB/W mice: Comparison with medroxyprogesterone and ethinyl estradiol. Autoimmunity 1991;9:21–32.
Harada M, Okamoto T, Omoto K, Tamada K, Takenoyama M, Hirashima C, Ito O, Kimura G, Nomoto K: Specific immunotherapy with tumor-draining lymph node cells cultured with both anti-CD3 and anti-CD28 monoclonal antibodies. Immunology 1996;87:447–453.
Chomczynski P, Sachi N: Single step method of RNA isolation by acid guanidinium thiocyanate phenol chloroform extraction. Anal Biochem 1987;162:156–159.
Wyle FA, Kent JR: Immunosuppression by sex steroid hormones. I. The effect upon PHA and PPD stimulated lymphocytes. Clin Exp Immunol 1977;27:407–415.
Clemens LE, Sitteri PK, Stites DP: Mechanism of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy. J Immunol 1979;122:1978–1985.
Grossman CJ: Interactions between the gonadal steroids and the immune system. Science 1985;227:257–261.
Coffman R, Varkila K, Scott P, Chatelain R: Role of cytokines in the differentiation of CD4+ T cell subsets in vivo. Immunol Rev 1991;123:189–207.
Lubaroff D, Waksman H: Bone marrow as source of cells in reactions of cellular hypersensitivity. II. Identification of allogenic or hybrid cells by immunofluorescence in passively transferred tuberculin reactions. J Exp Med 1968;128:1437–1447.
Matsushima GK, Gilmore W, Casteel N, Freliger J, Stohlman SA: Evidence for a subpopulation of antigen presenting cells specific for the induction of the delayed-type hypersensitivity response. Cell Immunol 1989;119:171–181.
Lou H, Kodama T, Zhao Y, Maurice P, Wang Y, Katz N, Foegh M: Inhibition of transplant coronary arteriosclerosis in rabbits by chronic estradiol treatment is associated with abolition of MHC II antigen expression. Circulation 1996;94:3355–3361.
Saito S, Foegh M, Notomura N, Lou H, Kent K, Ramwell P: Estradiol inhibits allograft-inducible major histocompatibility complex class II antigen expression and transplant arteriosclerosis in the absence of immunosuppression. Transplantation 1998;66:1424–1431.
Tabibzadeh S, Sivarajah A, Carpenter D, Ohlsson-Wilhelm M, Satyaswaroop P: Modulation of HLA-DR expression in epithelial cells by interleukin-1 and estradiol-17β. J Clin Endocrinol Metab 1990;71:740–747.
Scott P: Selective differentiation of CD4+ T helper cell subsets. Curr Opin Immunol 1993;5:391–397.
Khirabadi BS, Foegh ML, Ramwell W: Urine immunoreactive thromboxane B2 in rat cardiac allograft rejection. Transplantation 1985;39:6–8.
Mosmann TR, Sad S: The expanding universe of T cell subsets: Th1, Th2 and more. Immunol Today 1996;17:138–146.
Powrie F, Menon S, Coffman L: Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol 1993;23:3043–3049.
de Waal Malefyt R, Yssel H, Vries J: Direct effects of IL-10 on subsets of human CD4 T cell clones and resting T cells. J Immunol 1993;150:4754–4765.
Schwarz A, Grabbe S, Reimann H, Aragane Y, Simson M, Manon S, Andrade S, Luger A, Zoltnik A, Schwarz T: In vivo effects of interleukin-10 on contact hypersensitivity and delayed-type hypersensitivity reactions. J Invest Dermatol 1994;103:211–216.
Chernoff E, Granowitz V, Shapiro L, Vannier E, Lonnemann G, Angel B, Kennedy S, Rabson R, Wolff M, Dinarello A: A randomized, controlled trial of IL-10 in humans: Inhibition of inflammatory cytokine production and immune responses. J Immunol 1995;154:5492–5499.
Evan M, MacLaughlin S, Marvin R, Abdou N: Estrogen decreases in vitro apoptosis of peripheral blood mononuclear cells from women with normal menstrual cycles and decreases TNF-α production in SLE but not in normal cultures. Clin Immunol Immunopathol 1997;82:258–262.
Huber SA, Pfaffle B: Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3. J Virol 1994;68:5126–5132.
Elenkov IJ, Hoffman J, Wilder RL: Does differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period? Mol Med Today 1997;3:379–383.
Masi AT: Sex hormones and rheumatoid arthritis: Cause or effect relationships in a complex pathophysiology? Clin Exp Rheumatol 1995;13:227–240.
Lin L, Chen Y, Chou C, Hsieh K, Chiang B: Dysregulation of T helper cell cyotkines in autoimmune prone NZB × NZW F1 mice. Scand J Immunol 1995;42:466–472.
Lahita RG: Sex hormones as immunomodulators of disease. Ann NY Acad Sci 1993;685:278–287.
Carlsten H, Nilsson N, Jonsson R, Backman R, Holmdahl R, Tarkowski A: Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol 1992;144:190–202.
Falcone V, Marelli P, Zolfino I, Campa M: BCG-activated NK cells regulate the antibody response to SRBC and restore immune reactivity to PPD in BCG-infected mice. Immunol Lett 1993;36:295–299.
Seaman W, Blackman M, Gindhart T, Roubinian J, Loeb J, Talal N: β-Estradiol reduces natural killer cells in mice. J Immunol 1978;121:2193–2198.
Trinchieri G: Interleukin-12: A proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 1995;13:251–276.
Taube M, Svensson L, Carlsten H: T lymphocytes are not the target for estradiol-mediated suppression of DTH in reconstituted female severe combined immunodeficient (SCID) mice. Clin Exp Immunol 1998;114:147–153.
Abbas AK, Murphy KM, Sher A: Functional diversity of helper T lymphocytes. Nature 1996;383:787–793.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.