Effects of the Estrous Cycle and Ovarian Hormones on Central Expression of Interleukin-1 Evoked by Stress in Female Rats

Abstract

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.

Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease

“…First, steady-state levels of neuroinflammation appear to escalate in response to distinct stress challenges. Importantly, the nature of the neuroimmune response evoked by stress depends on key features of the individual, including genetic differences (sex and other genomic differences) and/or hormonal status of the subject (Arakawa et al , 2014, Duma et al , 2010, Hodes et al , 2014). Experiential factors, such as social experiences, appear to be particularly important drivers of neuroimmune differences across a wide range of species.…”

“…For instance, activation of the HPA axis does not lead to the sole release of GC hormone from the adrenal gland, but instead leads to the release of a multitude of other hormonal mediators, many of which have immunomodulatory properties (Deak, 2008). Notably, progesterone is a precursor steroid that is enzymatically and rapidly converted to corticosterone in the adrenal glands, and yet plasma progesterone evinces a rapid surge that parallels plasma corticosterone in both male (Hueston and Deak, 2014) and female (Arakawa et al , 2014) rats. Additionally, there are virtually no manipulations that adequately discriminate between corticosterone and progesterone action since metyrapone administration or ADX ablate both corticosterone and progesterone (Hueston and Deak, 2014), and most GC-selective antagonists do not adequately discriminate between corticosteroid and progestin receptors (Etgen and Barfield, 1986, Rupprecht et al , 1993).…”

“…Although very few studies have addressed sex differences in neuroimmune responses to stress, our lab recently completed a series of studies showing that ovariectomy led to (i) increased basal and stress-evoked expression of IL-1 in the PVN relative to sham-operated females, and that (ii) this effect was recovered by replacement of estradiol (Arakawa et al , 2014). Although we also observed some fluctuation in stress-dependent expression of IL-1 across the ovarian cycle (i.e., the IL-1 response in the PVN was less pronounced during metestrus), this latter effect requires additional follow-up studies to better understand the mechanism.…”

Stress and adolescent hippocampal neurogenesis: diet and exercise as cognitive modulators

“…162, 163, 164 Under conditions of severe and chronic stressor exposure however, not only does the HPA axis remain activated, but a neuroinflammatory milieu ensues within many brain structures including the hypothalamus and hippocampus. 165, 166, 167, 168, 169, 170, 171, 172 …”

Repeated exposure to two stressors in sequence demonstrates that corticosterone and paraventricular nucleus of the hypothalamus interleukin‐1β responses habituate independently

“…It can be noted, however, that females display a robust increase in IL-1β expression after footshock, an effect that varies significantly in response to ovarian hormones. 50 Although CORT habituation to restraint has been shown to occur similarly in males and females, 51 habituation to other stressors, such as the presently-used forced swim, remains to be examined and may proceed differently between the sexes.…”