Interleukin-6 (IL-6) and IL-6 receptor mRNA and protein have been reported in different brain regions under normal and pathophysiological conditions. Although much is known about the hypothalamic-pituitary-adrenal (HPA) axis stimulation after acute administration, less is known about the chronic effects of IL-6 on the function of the HPA axis. In the present study, we examined the function of the HPA axis in transgenic mice in which constitutive expression of IL-6 under the control of the glial fibrillary acidic protein (GFAP) promoter was targeted to astrocytes in the CNS. GFAP-IL6 mice heterozygous or homozygous for the IL-6 transgene had normal basal plasma corticosterone levels but, after restraint stress, showed abnormally increased levels in a gene dose-dependent manner. The increased plasma corticosterone levels in the IL-6 transgenic mice were associated with increased adrenal corticosterone content and hyperplasia of both adrenal cortex and medulla. Notably, plasma adrenocorticotrophic hormone (ACTH) levels and pituitary ACTH content were either not changed or decreased in these mice, whereas plasma arginine vasopressin (AVP) was increased, supporting a role for AVP in response to acute immobilization stress. The reduced ACTH response together with the adrenal hyperplasia in the IL-6 transgenic mice suggests direct activation at the level of the adrenal gland that may be directly activated by AVP or sensitized to ACTH. A similar mechanism may play a role in the blunted ACTH response and elevated corticosterone levels under pathophysiological conditions observed in humans with high brain levels of IL-6.