Interleukin-1ß (IL-1ß) is crucial mediator of adaptative stress response of the hypothalamic-pituitary-adrenal (HPA) axis. The potential relationship between stress and brain IL-1ß has not been elucidated. Central and systemic administration of IL-1ß enhanced HPA axis activity. We examined the role of IL-1ß in ACTH and corticosterone (CORT) secretion and parallel alterations of IL-1ß in plasma and brain structures involved in HPA axis regulation. Experiments were performed on male Wistar rats. Non-stressed groups of rats were injected i.p. IL-1ß, IL-1ß receptor antagonist and saline. Stressed rats were exposed to 10 min restraint twice a day for 3 days. Twenty-four hour after the last stress period rats were treated like non-stressed. After decapitation trunk blood was collected and the brain prefrontal cortex, hippocampus and hypothalamus were excised and frozen at -70°C. Total CORT, ACTH and IL-1ß levels were determined using commercially available kits. Western blot analyses were performed on brain structures. Under basal conditions IL-1ß considerably increased plasma IL-1ß level, in a time dependent manner, more potently 1 h than 2 h following administration. By contrast plasma ACTH and CORT levels were more strongly enhanced at 2 h than 1 h after IL-1ß injection. This indicates that the most potent increase in plasma IL-1ß levels preceded a similar enhancement of ACTH and CORT secretion. IL-1ß receptor antagonist abolished the increase in ACTH and CORT responses to exogenous IL-1ß. Prior repeated stress increased IL-1ß production and sensitized ACTH and CORT responses to exogenous IL-1ß. Repeated stress also enhanced IL-1ß level in brain structures involved in HPA axis regulation and intensified this increase induced by exogenous IL-1ß. These results indicate the selective modulatory role of IL-1ß in HPA axis activation under basal and stress conditions. Financed by European Regional Development Fund, grant POIG 01.01.02-12-004/09-00.