Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation

Abstract

Background Norepinephrine (NE) is one of the primary catecholamines of the sympathetic nervous system released during a stress response and plays an important role in modulating immune function. NE binds to the adrenergic receptors on immune cells, including T cells, resulting in either suppressed or enhanced function depending on the type of cell, activation status of the cell, duration of NE exposure and concentration of NE. Here, we aim to analyze the effects of NE on the functionality of naïve (Tn), central memory (Tcm) and effector memory (Tem) CD8 T cells. Methods We isolated CD8 T cell subsets from healthy human adults and treated cells in vitro with NE (1×10−6 M) for 16 hours; we then stimulated NE treated and untreated CD8 T cell subsets with antibodies for CD3 and CD28 for 24 and 72 hours. We assessed the level of beta-2 adrenergic receptor (ADRB2) expression in these cells as well as global gene expression changes in NE treated Tcm cells by microarray analysis. Altered expressed genes after NE treatment were identified and further confirmed by RT-qPCR, and by ELISA for protein changes. We further determined whether the observed NE effects on memory CD8 T cells are mediated by ADRB2 using specific adrenergic receptor agonist and antagonists. Finally, we examined the levels of mRNA and protein of the NE-induced genes in healthy adults with high serum levels of NE (>150 pg/mL) compared to low levels (<150 pg/mL). Results We found that memory (Tcm and Tem) CD8 T cells expressed a significantly higher level of ADRB2 compared to naïve cells. Consequently, memory CD8 T cells were significantly more sensitive than naïve cells to NE induced changes in gene expressions in vitro. Global gene expression analysis revealed that NE induced an elevated expression of inflammatory cytokines and chemokines in resting and activated memory CD8 T cells in addition to a reduced expression of growth-related cytokines. The effects of NE on memory CD8 T cells were primarily mediated by ADRB2 as confirmed by the adrenergic receptor agonist and antagonist assays. Finally, individuals with high serum levels of NE had similar elevated gene expressions observed in vitro compared to the low NE group. Conclusions Our results demonstrate that NE preferentially modulates the functions of memory CD8 T cells by inducing inflammatory cytokine production and reducing activation-induced memory CD8 T cell expansion.

Particulate Matter Exposure and Stress Hormone Levels

“…By binding to various cellular receptors, epinephrine and norepinephrine may induce profound metabolic changes via increased glycolysis and lipolysis, hypertensive changes via arterial smooth muscle constriction and increased cardiac output, 43 and proinflammatory changes via increased expression of proinflammatory cytokines. 44 Last, our results suggest that PM exposure may stimulate the secretion of melatonin, a hormone that regulates circadian cycle and has multiple cardioprotective properties. 45 It has also been suggested that melatonin has antihypertensive effects probably because of its anti-inflammatory and reactive oxygen species scavenging properties, and its capability in improving endothelial function and interacting with central and peripheral nervous system.…”

Effects of cold stress andSalmonellaHeidelberg infection on bacterial load and immunity of chickens

“…Regarding stress effects on immune cells, our data suggested that (1) glucocorticoid seem to be the common link between the effects of stress on immunity; in fact, many of the effects on circulating leukocytes described during stress may be ascribed to increased levels of this hormone (Costa-Pinto & Palermo-Neto, 2010); (2) despite the well-known immunosuppressive properties of glucocorticoids, it is known that these hormones also possess opposing effects that emphasize a bimodal hormonal regulation of the immune responses (Petrella et al, 2014); (3) a growing body of evidence indicates that the SNS modulates the immune system functions; however, the effect of NOR on immune cells appears to be more complex, as NOR can have either a stimulatory or inhibitory effect depending on the type of immune cell, their activation status, the duration of NOR exposure and the dose of NOR employed (Slota et al, 2015).…”

“…A significant decrease in CD8 + cell numbers was also found on ED21 in birds of the PCS group of this study. Recent work using in vitro NOR treatment and CD8 + T cells (Slota et al, 2015) showed a catecholamine-induced reduction in the expression of IFN-γ and IL-2 in NOR treated memory CD8 + T cells; according to these authors, the decreased productions of IL-2 and IFN-γ might have contributed to the modest decrease in the immune cell number found in the NOR-treated cells. These findings suggest that NOR might play a pivotal role in altering the proliferation of memory CD8 + T cells.…”

A Neurological Perspective upon Diabetes and Obesity, What They Are, and How They Can Be Measured

“…Moreover such a hypothesis considers the influence of genotype in isolation. It ignores the potential influence of phenotype (the sympathetic stress response) which influences levels of essential minerals, vitamins and cofactors; lowers levels of T-cells and immunochemicals in response to a particular stress or stressor [38] [39]; and facilitates the onset and progression of a particular viral infection, the direct or indirect establishment of an autoimmune response [25] and the subsequent development of type 1 diabetes.…”