Interleukin-1β (IL-1β) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1β could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1β derives from a 31-kD precursor (pro-IL-1β) that is processed by IL-1β-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1β in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 μg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1β (rrIL-1β) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1β or IL-6, which was similar to that of WT mice after rrIL-1β injection. After lypopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1β and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1β nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1β processed by non-ICE proteases.