Endogenous glucocorticoids down regulate central effects of interleukin-1 β on body temperature and behaviour in mice

doi:10.1016/0006-8993(95)01041-9

Brain Research

Volume 702, Issues 1–2, 8 December 1995, Pages 173-180

https://doi.org/10.1016/0006-8993(95)01041-9 Get rights and content

Abstract

Adrenalectomy sensitizes laboratory animals to the pyrogenic and behavioural effects of proinflammatory cytokines. To determine whether these effects are mediated by central sites of action of glucocorticoids, interleukin-1 β was injected intracerebroventricularly (i.c.v.) in adrenalectomized mice with or without corticosterone supplementation and in mice pretreated i.c.v. with the glucocorticoid II receptor antagonist RU38486. Adrenalectomized mice were more sensitive to the depressing effects of i.c.v. IL-1 β on body temperature and social exploration than sham-operated mice. Corticosterone supplementation reversed the increased sensitivity to the low (300 pg/mouse) but not to the high dose (900 pg/mouse) of IL-1 β. Central administration of RU38486 (0.5 – 1 μg/mouse) mimicked the effects of adrenalectomy on behaviour but not on body temperature. These results suggest that endogenous glucocorticoids released in response to IL-1 β act in the brain to modulate the sensitivity of the cellular targets of this cytokine.

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For example, there is seasonal modulation of the sickness response after bacterial lipopolysaccharide (LPS) challenge in birds and mammals (Bilbo et al., 2002; Owen-Ashley et al., 2006, 2008; Owen-Ashley and Wingfield, 2006), although there are exceptions to this rule (for e.g., Hegemann et al., 2012). This variation seems to be influenced by a combination of proximate factors that include testosterone (in males; Ashley et al., 2009), melatonin (Bilbo and Nelson, 2002), glucocorticoids (Goujon et al., 1995a, 1995b), insulin (Carlton and Demas, In press) and body condition (Carlton and Demas, 2015; Owen-Ashley et al., 2006, 2008; Owen-Ashley and Wingfield, 2006), which is partially mediated by leptin (Carlton and Demas, 2014)—a satiety hormone produced from adipose cells. From an ultimate perspective, sickness behavior represents an “opportunity cost” and thus conflicts with the expression of other activities important for reproductive and growth functions (sexual and social behavior, territorial defense, parental care, etc.; Ashley and Wingfield 2012; Owen-Ashley and Wingfield 2007).
Multidirectional interactions among the immune, endocrine, and nervous systems have been demonstrated in humans and non-human animal models for many decades by the biomedical community, but ecological and evolutionary perspectives are lacking. Neuroendocrine-immune interactions can be conceptualized using a series of feedback loops, which culminate into distinct neuroendocrine-immune phenotypes. Behavior can exert profound influences on these phenotypes, which can in turn reciprocally modulate behavior. For example, the behavioral aspects of reproduction, including courtship, aggression, mate selection and parental behaviors can impinge upon neuroendocrine-immune interactions. One classic example is the immunocompetence handicap hypothesis (ICHH), which proposes that steroid hormones act as mediators of traits important for female choice while suppressing the immune system. Reciprocally, neuroendocrine-immune pathways can promote the development of altered behavioral states, such as sickness behavior. Understanding the energetic signals that mediate neuroendocrine-immune crosstalk is an active area of research. Although the field of psychoneuroimmunology (PNI) has begun to explore this crosstalk from a biomedical standpoint, the neuroendocrine-immune-behavior nexus has been relatively underappreciated in comparative species. The field of ecoimmunology, while traditionally emphasizing the study of non-model systems from an ecological evolutionary perspective, often under natural conditions, has focused less on the physiological mechanisms underlying behavioral responses. This review summarizes neuroendocrine-immune interactions using a comparative framework to understand the ecological and evolutionary forces that shape these complex physiological interactions.
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Males of many vertebrate species are typically more prone to disease and infection than female conspecifics, and this sexual difference is partially influenced by the immunosuppressive properties of testosterone (T) in males. T-induced immunosuppression has traditionally been viewed as a pleiotropic handicap, rather than an adaptation. Recently, it has been hypothesized that suppression of sickness behavior, or the symptoms of infection, may have adaptive value if sickness interferes with the expression of T-mediated behaviors important for male reproductive success. We conduct a classic hormone replacement experiment to examine if T suppresses sickness behavior in a seasonally-breeding songbird, Gambel's white-crowned sparrow (Zonotrichia leucophrys gambelii). Triggered experimentally by bacterial lipopolysaccharide (LPS), sickness behavior includes decreased activity, anorexia, and weight loss. Gonadectomized (GDX) males that were treated with silastic implants filled with T exhibited suppression of behavioral and physiological responses to LPS compared to GDX and sham-GDX controls given empty implants. Sickness responses of control groups were statistically indistinguishable. T-implanted birds had significantly higher plasma T than control groups and levels were within the range associated with aggressive interactions during male-to-male contests. These findings imply that suppression of sickness behavior could occur when T is elevated to socially-modulated levels. Alternatively, it is possible that this suppressive effect is mediated through a stress-induced mechanism, as corticosterone levels were elevated in T-implanted subjects compared to controls. We propose that males wounded and infected during contests may gain a brief selective advantage by suppressing sickness responses that would otherwise impair competitive performance. The cost of immunosuppression would be manifested in males through an increased susceptibility to disease, which is presumably offset by capitalizing upon limited reproductive opportunities.
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That is, both chronic stress and ADX facilitated the behavioral effects of IL-1: When IL-1 was administered following chronic (but not acute) stress, its detrimental effect on social exploration and appearance was significantly enhanced [254]. Several studies showed that both ADX and blockade of GC receptors by RU-38486 amplified and prolonged the behavioral effects of IL-1 administration: The decrease in social exploration and increase in body temperature, induced by either peripherally or centrally administered IL-1, were enhanced by ADX or RU-38486 [105], and, under these treatments, ICV administration of low IL-1 doses, which do not cause behavioral alterations in non-treated mice, resulted in reduced social exploration [104]. Corticosterone supplementation abolished the augmenting effect of ADX for low IL-1 doses, reduced it for moderate doses, and had no effect on higher doses [104,105].
Ample evidence demonstrates that the pro-inflammatory cytokine interleukin-1 (IL-1), produced following exposure to immunological and psychological challenges, plays an important role in the neuroendocrine and behavioral stress responses. Specifically, production of brain IL-1 is an important link in stress-induced activation of the hypothalamus-pituitary-adrenal axis and secretion of glucocorticoids, which mediate the effects of stress on memory functioning and neural plasticity, exerting beneficial effects at low levels and detrimental effects at high levels. Furthermore, IL-1 signaling and the resultant glucocorticoid secretion mediate the development of depressive symptoms associated with exposure to acute and chronic stressors, at least partly via suppression of hippocampal neurogenesis. These findings indicate that whereas under some physiological conditions low levels of IL-1 promote the adaptive stress responses necessary for efficient coping, under severe and chronic stress conditions blockade of IL-1 signaling can be used as a preventive and therapeutic procedure for alleviating stress-associated neuropathology and psychopathology.
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Given that cytokines are active at low concentrations, IL-1β synthesis may often be below the detection limit of anatomical techniques, such as immunocytochemistry and in situ hybridization [39]. In this respect, it is of interest to note that glucocorticoids inhibit both the expression and the action of IL-1β in the CNS [40,41]. Therefore, stress to the experimental animal should be limited to a strict minimum when studying brain IL-1β expression and action.
The brain parenchyma has long been considered immunologically privileged based on the lack of a true lymphoid system. It is, however, clear now that brain infection or injury elicits innate immune responses including the release of cytokines, such as interleukin-1β (IL-1β). Interestingly, low levels of IL-1β are already present in the developing and adult brain in the absence of any infection or injury, indicating that this cytokine plays a role in the modulation of central nervous system functioning. The aim of this chapter is to provide some insight into the different roles IL-1β may play in the brain in the absence of neuropathology and to outline the difficulties and pitfalls associated with the study of brain IL-1β expression and action. Brain IL-1β expression during postnatal development has been hypothesized to regulate neuronal survival in a nerve growth factor (NGF)-dependent way. It is becoming clear that the constitutive low expression of IL-1β in the adult hippocampus plays a role in spatial learning and memory processes, possibly through its role in maintaining long-term potentiation. The circadian variation in expression of IL-1β in the adult forebrain is proposed to play a role in the physiological regulation of sleep, probably as a circulating factor in the cerebrospinal fluid. Constitutive IL-1β expression in neuroendocrine hypothalamic nuclei might act as a true neuropeptide and mediate neuroendocrine responses in response to physical stressors. The peripheral administration of bacterial lipopolysaccharides induces de novo IL-1β synthesis at the blood–brain interface without disrupting the blood–brain barrier. This transient IL-1β production at the blood–brain interface in response to peripheral immune stimuli is thought to constitute a signal mediating behavioral changes during infectious and inflammatory diseases. In conclusion, it is recognized increasingly that IL-1β production and action in the brain is involved in various neurobiological responses that are distinct from its classical role in mediating cellular responses to infection and injury.
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Endogenous glucocorticoids down regulate central effects of interleukin-1 β on body temperature and behaviour in mice

Abstract

Physiol. Behau.

Psychoneuroendocrinology

Blood

Mol. Brain Res.

Brain Behav. Immunity

Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1

Science

Adrenalectomy sensitizes mice to lethal effects of interleukin-1 and tumor necrosis factor

J. Exp. Med.

CRF is not involved in the behavioural effects of peripherally injected interleukin 1 in the rat

Neurosci. Res. Commun.

Interleukin-1 receptor antagonist blocks effects of IL-1 α and IL-1 β on social behavior and body weight in mice

Neurosci. Res. Commun.

Endotoxin-induced fever is modulated by endogenous glucocorticoids in rats

Am. J. Physiol., Regul. Integr. Comp. Physiol.

Adrenocorticotropin, β-endorphin and corticosterone secretion in the Brattleboro rat

Endocrinology

Interleukin-1 type II receptor: A decoy target for IL-1 that is regulated by IL-4

Science

The function of glucocorticoids in thermogenesis

Implication of brain corticosteroids receptor diversity for the adaptation syndrome concept

Corticosterone regulates behavioral effects of lipopolysaccharide and interleukin-1 β in mice

Am. J. Physiol.

Effect of E. coli endotoxin on temperature, oxygen consumption and brown adipose tissue thermogenesis in rat and mice

Biosci. Reports

Endotoxin-induced corticotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is mediated centrally by interleukin-1

Endocrinology

Fever: role of pyrogens and cryogens

Physiol. Rev.