Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol

J Reprod Immunol. Oct-Nov 2001;52(1-2):113-27. doi: 10.1016/s0165-0378(01)00117-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Diethylstilbestrol / metabolism*
  • Diethylstilbestrol / pharmacology
  • Estradiol / metabolism*
  • Estradiol / pharmacology
  • Estrogens, Non-Steroidal / metabolism*
  • Estrogens, Non-Steroidal / pharmacology
  • Female
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Lymphocytes / cytology
  • Lymphocytes / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Orchiectomy
  • Ovariectomy
  • RNA, Messenger / metabolism
  • Spleen / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Up-Regulation*


  • Estrogens, Non-Steroidal
  • RNA, Messenger
  • Estradiol
  • Diethylstilbestrol
  • Interferon-gamma