In utero DES exposure may permanently alter the “cytokine programming” of lymphocytes
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:
- estrogens upregulate IFN-gamma secretion, a vital immunoregulatory cytokine,
- and inappropriate exposure of developing fetus to DES may permanently alter the “cytokine programming” of lymphocytes.
- Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol, US National Library of Medicine National Institutes of Health, Journal of reproductive immunology, NCBI pubMed PMID: 11600182, 2001 Oct-Nov.
- Interferon gamma image credit wikimedia.