Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol.
Gamma-interferon (IFN-gamma) plays an important role in the maintenance of immune homeostasis by regulating the functions of all key cells of the immune system. Pathologically, IFN-gamma has been implicated in several autoimmune diseases. Since estrogens affect autoimmunity, we investigated whether immunomodulatory estrogenic hormones affects IFN-gamma. Concanavalin-A-stimulated splenic lymphocytes from orchiectomized or ovariectomized C57BL/6 mice exposed to estrogen for 3-5 months secreted higher levels of IFN-gamma protein compared to controls. This increase is, in part, due to increased levels of IFN-gamma mRNA. Kinetic studies suggested that splenic lymphocytes from estrogen-treated gonadectomized mice had increased IFN-gamma mRNA and protein as early as 6-12 h of culture. Estrogen also increased the expression of co-stimulatory CD80 (B7-1) molecules on B cells. Since natural estrogen increases IFN-gamma, it became important to test whether diethylstilbestrol (DES, a synthetic estrogen which was given to millions of women) also alters IFN-gamma levels. Our initial investigatory studies show that prenatal mice exposed to DES had a normal ability to secrete IFN-gamma. However, a second exposure of these mice to DES (single dose of 1 microg/g.b.w), as late as 1-1.5 years of age, led to a pronounced increase in the number of IFN-gamma secreting cells and augmented secretion of IFN-gamma. Increased IFN-gamma secretion by splenic lymphocytes from these mice was noted even after stimulation with a submitogenic concentration of anti-CD3 antibodies with or without anti-CD28 antibodies. Cell mixing experiments suggested that the DES-induced increase in IFN-gamma secretion is due to hormonal effects on T cells but not on APC. Together our studies show that: (1) estrogens upregulate IFN-gamma secretion, a vital immunoregulatory cytokine, and (2) inappropriate exposure of developing fetus to DES may permanently alter the "cytokine programming" of lymphocytes.
Karpuzoglu-Sahin
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Center for Molecular Medicine and Infectious Diseases, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, VA 24060-0342, USA. ansrahmd@vt.edu
Hissong
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BD
Ansar Ahmed
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D000818:Animals; D002478:Cells, Cultured; D004054:Diethylstilbestrol / Q000378:metabolism* / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation
D004968:Estrogens, Non-Steroidal; D012333:RNA, Messenger; D004958:Estradiol; D004054:Diethylstilbestrol; D007371:Interferon-gamma