The role of interleukin-6 in stress-induced hyperthermia and emotional behaviour in mice

Abstract

Psychological stress influences behaviour as well as autonomic functions such as body temperature. The mechanism that induces hyperthermia during stress is unknown. A recent hypothesis suggests that interleukin-6 (IL-6), an endogenous pyrogen, elevates body temperature during stress. To investigate the role of IL-6 during stress, we measured mRNA levels of IL-6 by quantitative PCR in various tissues 60 min after exposure of mice to open field stress. IL-6 mRNA was elevated in the hypothalamus three-fold and in the pituitary two-fold. However, there was no difference between the increase in body temperature after exposure to 60 min open field stress in wild-type controls (35.2±0.6–37.3±0.5 °C) and IL-6-deficient animals (34.8±0.4–37.0±0.3 °C). In contrast to body temperature, emotional behaviour differed between wild-type controls and IL-6-deficient mice. IL-6-deficient animals showed higher locomotor activity in an open field and lower levels of exploration of the open arms of the elevated plus maze than control animals. These data suggest that IL-6 plays an important role in the control of emotionality, but not in the regulation of body temperature after psychological stress.

Introduction

Cytokines mediate the sickness behaviour that accompanies infection and inflammation. Lethargy and anorexia in sepsis are induced by the cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α as shown by gene deletion studies [3]. Furthermore, the administration of exogenous cytokines leads to a response that mimics behaviour in sepsis [24]. Repeated cytokine induction as a result of infection is considered a potential trigger of major depression [24]. Indeed, elevated serum levels of cytokines such as IL-6 were found in patients with major depression [35]. A role of cytokines in the development of depression is further supported by the finding that psychological stress, another trigger of depressive disorders, also induces cytokine expression. Plasma concentrations of IL-6 are increased upon psychological stress in laboratory animals and humans [27], [30], [47], [51]. Several reports showed that psychological stress increases hepatic IL-6 expression [20], [22]. The expression of IL-6 in other tissues involved in the stress response is unclear.

Psychological stress influences various behavioural, endocrine, autonomic, and immune functions, and the response to psychological stress resembles the acute phase reaction that is induced by infection or inflammation. The two have the induction of acute phase proteins and elevation of body temperature in common [2], [23], [34], [43]. Hyperthermia due to psychological stress has been conserved in the phylogeny. For example, coping with stress or exposure to novel environments can raise the core temperature by as much as 2 °C in rats [36], [46]. A similar phenomenon is observed in species as different as lizards and humans [38]. This stress-induced hyperthermia is an integral part of the organism’s response to situations perceived as distressing and may serve to activate immune defense. Its robust occurrence makes it a reliable experimental paradigm in anxiety and psychological stress research [29], [31]. However, apart from the fact that the phenomenon is mediated by the autonomic nervous system, little is known about the underlying mechanism. In sepsis and local inflammation, IL-6 is considered to be a final common mediator in the cytokine cascade to febrogenesis [8], [26]. The well-documented rise in plasma IL-6 concentrations in stress has suggested that IL-6 may participate in the stress-induced increase in body temperature [38], [44], [47]. Further evidence for this hypothesis comes from the reduction in both IL-6 plasma concentrations and body temperature by β-adrenergic-receptor blockers [44], [47]. IL-6 not only regulates the body temperature but also exerts various behavioural effects, including anorexia and inhibition of avoidance learning, when it is overexpressed or injected into the ventricles [18], [42]. However, the role of endogenous IL-6 in emotional behaviour during psychological stress is incompletely understood.

To investigate the role of IL-6 in the response to psychological stress, we quantified IL-6 expression in various tissues in a mouse model of psychological stress. The results suggest a role in the brain and in peripheral endocrine organs. In the absence of IL-6, mice had the same increase in body temperature induced by open field stress but had a higher level of anxiety in the elevated plus maze than control mice. The dependency on IL-6, therefore, distinguishes two components of the stress response: IL-6-independent hyperthermia and IL-6-mediated emotional behaviour.