We investigated whether interleukin-6 (IL-6) could cause the release of corticosterone by a direct interaction with the adrenal gland. Primary cultures of rat adrenal glands were obtained by dispersion with collagenase and incubated for 24 h with different doses of IL-6. Levels of corticosterone were measured by competitive protein binding assay. A significant (P less than 0.025) dose-dependent increase in corticosterone levels was seen at all doses used. Time course experiments demonstrated that IL-6 stimulated corticosterone release over a period of 24 h but not after 12 or 3 h. The stimulation of adrenal cells with different doses of ACTH1-24 and 40 U/ml of IL-6 showed a synergistic effect when IL-6 was combined with low concentrations of ACTH1-24 (2 and 20 pmol/l). This effect was not evident at higher doses. Our results suggest that IL-6 may act at different levels of the hypothalmic pituitary adrenal axis. Moreover the finding of a synergistic effect with ACTH1-24 indicates that IL-6 could play a role in the long term response to stress.