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Mechanisms of Behavioral and Neuroendocrine Effects of Interleukin‐1 in Mice
Author(s) -
NEVEU PIERRE J.,
LIÈGE STÉPHANE
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb05382.x
Subject(s) - immune system , beta (programming language) , endocrinology , stimulation , medicine , receptor , interleukin , biology , chemistry , immunology , cytokine , computer science , programming language
A bstract : Interleukin‐1β is a key molecule in brain‐immune interactions that, apart from its immune effects, stimulates the hypothalamo‐pituitary‐adrenal (HPA) axis and induces behavioral alterations. However, its physiological role during stress responses remain to be elucidated. The possible mechanisms involved in IL‐1‐mediated stimulation of the HPA axis during stress were assessed by using different approaches. They were first studied in mice deficient for the IL‐1β‐converting enzyme (ICE) gene. Mature IL‐1β derives from a precursor, the pro‐IL‐1β, devoid of any conventional signal sequence that is mainly processed by ICE. After immune or stress stimulation, ICE‐deficient mice were shown to have a hyperactive HPA axis and to able to produce immunoreactive IL‐1β. This indicates that the greater reactivity of the HPA axis could result from a higher sensitivity to non‐ICE‐matured IL‐1β, as suggested by a higher basal transcription of hypothalamic IL‐1 receptor type I (IL‐1 RI) in ICE‐deficient mice. The biological effects of IL‐1β are mediated by IL‐1 RI associated with the IL‐1 receptor accessory protein (IL‐1RAcP). IL‐IRAcP is an essential component for IL‐1 action at the periphery, but its role in the brain is not well known. Therefore, the effects of i.c.v. IL‐1β were studied in IL‐1RAcP‐deficient mice. In normal mice, i.c.v. IL‐1β depresses peripheral immune responses, induces the production of plasma IL‐6, and stimulates the HPA axis. None of these effects were observed in IL‐1RAcP‐deficient mice, indicating that IL‐1RAcP is necessary for the induction of the main neuroendocrine and immune effects of central IL‐1β. In normal mice, the role of IL‐1β was assessed by pretreating the animal with the IL‐1 receptor antagonist (IL‐1Ra). IL‐1Ra did modify the activation of the HPA axis observed during stress, except when the animals were previously sympathectomized. This suggests that the sympathetic nervous system can downregulate the IL‐1β‐induced stimulation of the HPA axis. Finally, the modulation of the production and physiological activities of IL‐1 were studied in normal mice, taking advantage of interindividual differences in brain‐immune interactions linked to cerebral lateralization. Behavioral/brain lateralization was shown to be related to behavioral response to peripheral administration of IL‐1, and to the production of IL‐1 and IL‐6 in response to LPS. This suggests that cytokines, and especially IL‐1β, may represent one of the factors responsible for interindividual differences in brain‐immune interactions.