Effects of the estrous cycle and ovarian hormones on central expression of interleukin-1 evoked by stress in female rats

Exposure to stressors such as foot shock (FS) leads to increased expression of multiple inflammatory factors, including the proinflammatory cytokine interleukin-1 (IL-1) in the brain. Studies have indicated that there are sex differences in stress reactivity, suggesting that the fluctuations in gonadal steroid levels across the estrous cycle may play a regulatory role in the stress-induced cytokine expression. The present studies were designed to investigate the role of 17-β-estradiol (E₂) and progesterone (Pg) in regulating the cytokine response within the paraventricular nucleus (PVN) of the hypothalamus through analysis of gene expression with real-time RT-PCR. Regularly cycling female rats showed a stress-induced increase in PVN IL-1 levels during the diestrous, proestrous, and estrous stages. During the metestrous stage, no change in IL-1 levels was seen following FS; however, estrogen receptor (ER)-β levels did increase. Ovariectomy resulted in an increase in PVN IL-1 levels, which was attenuated by treatment with estradiol benzoate (10 or 50 μg), indicating an E₂-mediated anti-inflammatory effect. Ovariectomized rats treated with Pg (500 or 1,250 μg) showed no alteration in IL-1 levels, but Pg did up-regulate ER-β gene expression. The results from the current study implicate a potential mechanism through which high availability of endogenous Pg during the metestrous stage increases ER-β sensitivity, which in turn attenuates the PVN IL-1 response to stress. Thus, the interaction between gonadal steroid hormones and their central receptors may exert a powerful inhibitory effect on neuroimmune consequences of stress throughout the estrous cycle.