Estrogen modulates neural–immune interactions through intracellular signaling pathways and antioxidant enzyme activity in the spleen of middle-aged ovariectomized female rats

Estrogen upregulates inflammatory signals through NF-κB, IFN-γ, and nitric oxide via Akt/mTOR pathway in the lymph node lymphocytes of middle-aged female rats

“…IFN-γ levels and its mRNA expression were found to be augmented in mouse splenocytes with estrogen stimulation [41]. Similar alterations were found in splenic lymphocytes where estrogen differentially altered lymphoproliferation and cytokine production influenced by estrogen receptors in vitro and in vivo [3,28,42].…”

“…Compromised immune status with advancing age may also facilitate development of mammary tumors in which there is a reduction in IL-2 and IFN-γ production by the lymphocytes of draining lymph nodes [30]. Ovariectomy-induced suppression of immune responses was similar to those found in lymphocytes from the spleen and may involve alterations in the expression of p-ERK/Total ERK and p-CREB/Total CREB [40,28](Supplementary data S1 and S2). Estrogen supplementation of OVX rats reversed OVX-induced suppression of immune responses that may be due to specific proliferation of IFN-γ producing cells associated with an increase in the number of antigenspecific CD4+ T cells mediated through ERα [22].…”

“…Initially, the middle-aged female rats were either sham operated or bilaterally OVX and after a week of recovery, 30-day placebo or estrogen pellets [17β-estradiol (0.6 μg or 300 μg), Innovative Research America, Florida, USA] were implanted subcutaneously in the nape of the neck. The doses were selected based on a preliminary study in our laboratory and a published study [28,29]. At the end of the treatment period, the animals were sacrificed by decapitation between 08:00 to 10:00 h. Trunk blood was collected in Falcon tubes, serum was isolated and used for hormone assay.…”

“…In addition, it may also involve a mitochondrial enzyme, cytochrome c oxidase, that is crucial to the electron transport chain and functional deficits in this enzyme is implicated in neurodegenerative disorders such as Parkinson′s disease and Alzheimer's disease [25][26][27]. Recently, we had demonstrated that estrogen modulates neuralimmune interactions in the spleen of estrogen-treated ovariectomized middle-aged rats [28]. The present study was designed to understand the role of estrogen on inflammatory immune responses and the involvement of associated signaling pathways in lymph nodes as there is limited information about its role in female reproductive aging.…”

In silicomodeling and simulation of neuroendocrine-immune modulation through adrenergic and 17β-estradiol receptors in lymphocytes show differential activation of cyclic adenosine monophosphate (cAMP)

“…In vitro studies from our laboratory have shown that adrenergic stimulation through α1-, α2- or β2- ARs using specific agonists non-specifically inhibit lymphoproliferation through distinct signaling pathways: α1-ARs mediated immunosuppressive effects by inhibiting IFN-γ production, α2-AR activated the NF-κB, p-Akt and NO pathways and β2-AR activation involved IL-6, NO and NF-κB signaling cascades mediating immunosuppression [17, 18]. On the other hand, treatment of lymphocytes with 17β-estradiol enhanced proliferation in a dose and receptor subtype specific manner through p-ERK, p-CREB and p-Akt involving IFN-γ and compensatory mechanisms including anitioxidant enzymes [4, 20]. Our studies have shown that co-treatment of lymphocytes with 17β-estradiol and adrenergic agonists lead to 17β-estradiol-mediated over-ride of adrenergic immunosuppression in a dose-dependent, AR-subtype independent manner [17, 18].…”