Administration of bacterial lipopolysaccharide (LPS) in rodents induces the release of pro-inflammatory cytokines [tumor necrosis factor (TNF), interleukin (IL)-1, IL-6] and of ACTH and corticosterone. IL-6 is probably an important cytokine in the interaction between the immune system and the hypothalamus-pituitary-adrenal (HPA) axis, but so far the role of IL-6 in lipopolysaccharide (LPS)-induced HPA activation has not been established unequivocally. We examined the effects of intraperitoneal administration of LPS (range 0.25-2000 pg/mouse) on plasma corticosterone, TNFalpha and IL-1alpha levels in IL-6-deficient (IL-6 -/-) and wildtype control (IL-6 +/+) mice. Plasma corticosterone levels increased within one hour in both mouse strains. The corticosterone response was significantly reduced in IL-6 -/- mice, but no differences in TNFalpha or in IL-1alpha plasma levels were found between the two strains. Next, we studied the involvement of IL-1alpha or TNFalpha in the responses to LPS in IL-6 -/- and IL-6 +/+ mice by infusion of recombinant human IL-1 receptor antagonist (IL-1ra), or by injection of anti-TNFalpha antibodies. Pretreatment with IL-1ra or with anti-TNFalpha did not affect the corticosterone response to LPS, neither in IL-6 -/-, nor in IL-6 +/+ mice. Our data suggest that in the stimulation of the HPA axis by LPS in mice blockade of either IL-1alpha or TNFalpha may be compensated for by other mediators. The reduced adrenal response after LPS administration found in IL-6 -/- mice indicates a distinct role for IL-6 in the activation of the HPA axis by LPS.