Mechanisms of behavioral and neuroendocrine effects of interleukin-1 in mice.

Interleukin-1 beta 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-1 beta-converting enzyme (ICE) gene. Mature IL-1 beta derives from a precursor, the pro-IL-1 beta, 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-1 beta. This indicates that the greater reactivity of the HPA axis could result from a higher sensitivity to non-ICE-matured IL-1 beta, 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-1 beta are mediated by IL-1 RI associated with the IL-1 receptor accessory protein (IL-1RAcP). IL-1RAcP 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-1 beta were studied in IL-1RAcP-deficient mice. In normal mice, i.c.v. IL-1 beta 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-1 beta. In normal mice, the role of IL-1 beta 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-1 beta-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-1 beta, may represent one of the factors responsible for interindividual differences in brain-immune interactions.