Dysregulation of the Th1/Th2 cytokine profile is associated with immunosuppression induced by hypothalamic-pituitary-adrenal axis activation in mice

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Abstract

Hypothalamic-pituitary-adrenal (HPA) axis activation-induced immunosuppression is associated with increased concentration of circulating corticosterone and impaired cellular immune responses. The purpose of this study was to investigate the effect of chronic HPA axis activation on the cellular immune response, Th1/Th2 cytokine profile, and concentration of corticosterone. Mice were divided into two groups: a control group comprised of healthy, untreated mice that received no stress, and an HPA axis-activated group that received stress through electric shock (ES). The delayed-type hypersensitivity reaction to dinitrofluorobenzene, splenocyte proliferative response to mitogens Concanavalin A and lipopolysaccharide, Th1 and Th2 profile, and TGF-β1 production were measured in plasma and in culture supernatants. The corticosterone concentration was also measured in plasma. In the ES group, elevated plasma corticosterone concentration was associated with immunosuppression and a significant decrease in plasma concentrations of IL-2, IL-4, and TGF-β1. In vitro IL-2 production in response to Con A was significantly lower in the ES group than in the control group. TGF-β1 production in nonstimulated and stimulated cultures in response to either mitogen was significantly lower in the ES group than in the control group. Plasma concentrations of IFN-γ and IL-10 did not differ significantly between groups. The concentrations of IFN-γ, IL-4, and IL-10 in the supernatants of splenocytes stimulated with either mitogen and IL-4 production by nonstimulated cells were significantly higher in the ES group than in the control group. These results suggest that corticosterone mediates the immunosuppression induced by HPA axis activation, and induces dysregulation of the Th1/Th2 cytokine profile.

Introduction

The interaction, coordination, and communication between the nervous, endocrine, and immune systems are mediated by common receptors to neurotransmitters, hormones, and cytokines [1], [2], [3]. The hypothalamic-pituitary-adrenal (HPA) axis is a key element of this communication pathway [3], [4]. Stressors can activate the HPA axis to produce glucocorticoids and the sympathetic nervous system to produce catecholamines [5]. Both glucocorticoids and catecholamines act as end effectors of the HPA axis [6], [7]. Glucocorticoid hormones regulate a wide range of biological processes, such as cell proliferation, inflammation, and immunity, and inhibit the trafficking of T, B, and NK cells, eosinophils, basophils, macrophages, and monocytes, also induce apoptosis in mature T and B cells, and peripheral blood lymphocytes. These events could explain, in part, the immunosuppression process associated with stress [8], [9], [10].

Th1 and Th2 cells represent two subpopulations of CD4+ T cells, which can be differentiated by their cytokine profiles [11]. Th1 cells produce interferon (IFN)-γ, which induces differentiation of CD4+ T cells to Th1 cells and inhibits the proliferation of Th2 cells [12]. In contrast, Th2 cells secrete both interleukin (IL)-4 and IL-10, which induce differentiation of Th2 cells and inhibit Th1 cells [13]. Th1 activation contributes to cell-mediated immunity whereas Th2 activation favors the humoral immune response [14], [15]. High concentrations of glucocorticoids stimulate the Th2 response and inhibit the Th1 response, and stress induces dysregulation of the Th1/Th2 cytokine profile [11].

Glucocorticoids inhibit the production of IL-2 and IFN-γ by Th1 cells, upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells, and increase the production of transforming growth factor (TGF)-β by phytohemmaglutinin (PHA)-stimulated T cells [16]. Increasing glucocorticoid levels works selectively by suppressing cellular immunity, and stimulating humoral immunity, rather than through generalized immunosuppression. Conditions associated with significant changes in glucocorticoid concentration, such as the introduction of acute or chronic stress, might affect the susceptibility or course of infection by modulating the Th1/Th2 balance [17]. The Th1/Th2 cytokine profile associated with stress-induced immunosuppression has not been studied in the HPA axis activation (elicited by electric stimulation) model.

We studied the effect of HPA axis activation on the cellular immune response, which we evaluated by measuring the delayed-type hypersensitivity (DTH) reaction to dinitrofluorobenzene (DNFB) and splenocyte proliferation in response to two mitogens. To establish a likely mechanism responsible for immunosuppression, we also determined the Th1/Th2 cytokine profile in plasma and splenocyte culture supernatants, and plasma corticosterone concentration from healthy and stressed BALB/c mice.

Section snippets

Animals

Eight-week-old male BALB/c mice weighing 20–25 g were selected and housed under standard environmental conditions (n = 10 per cage) at an ambient temperature of 22–24 °C under a 12:12 h light–dark cycle, and supplied with food and water ad libitum. Animals were manipulated according to the guide on the use and care of experimental animals (Mexican Official Norm NOM-062-ZOO-1999 published by SAGARPA in the Diario Oficial del Gobierno Mexicano paper on June 28, 2001).

HPA axis activation

HPA axis activation was

Delayed-type hypersensitivity reaction

Fig. 1 shows the values for the DTH reaction to DNFB in the different groups. The ear thickness increased less in the ES group (54.70 ± 22.83 μm) than in the control group (167.64 ± 31.58 μm, p < 0.001).

Proliferative assay

Fig. 2 shows the PI values. The PI in response to Con A (1 μg/mL) was significantly lower in the ES group (4.04 ± 2.74) than in the control group (13.80 ± 3.06, p < 0.001; Fig. 2A). The PI in response to LPS (3 μg/mL) was also significantly lower in the ES group (4.39 ± 2.34) than in the control group (10.42 ± 

Discussion

Stressor-induced HPA axis activation affects communication between the nervous, endocrine, and immune systems, the systems responsible for regulating physiological processes in mammals. In rodents, the immune system response to chronic stress conditions depends upon secretion of corticosterone, and increases in circulating corticosterone concentration inhibit the immune system [24]. Stress-induced activation of the medullary sympathetic adrenal and HPA axis stimulates secretion of

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