Interleukin-6 is an essential, corticotropin-releasing hormone-independentstimulator of the adrenal axis during immune system activation

Glucocorticoids play a critical role in control of the cytokine response af ter immune challenge. Conversely, cytokines modulate glucocorticoid product ion by the hypothalamic-pituitary-adrenal axis. To define the potency and m echanism of interleukin-6 (IL-6) for augmentation of adrenal function, we e xploited mice deficient in corticotropin-releasing hormone (CRH), IL-6, or both. Mice deficient in CRH action demonstrate severely impaired glucocorti coid production in response to psychological and metabolic challenge, but n ear normal responses to stressors that activate the immune system. In this paper, we demonstrate that IL-6 is essential for activation of the hypothal amic-pituitary-adrenal axis during immunological challenge in the absence o f hypothalamic: input from CRH. IL-6 receptors are present on pituitary cor ticotrophs and adrenocortical cells, consistent with the ability of IL-6 to bypass CRH in augmentation of adrenal function. Plasma corticosterone leve ls after bacterial lipopolysaccharide injection in mice deficient in CRH or IL-6 were significantly lower than in wild-type mice but significantly gre ater than in mice deficient in both CRH and IL-6. A second model of immune system activation using 2C11, an antibody to the T cell receptor, demonstra ted a normal corticosterone response in mice deficient in CRH or IL-6, but a markedly decreased response in mice deficient in both CRH and IL-6. Surpr isingly, the relative contribution of IL-6 for modulation of the adrenal re sponse to stress is greater in female than in male mice. This gender-specif ic difference in IL-6 action in mice suggests the utility of further analys is of IL-6 in determining the female predominance seen in many human inflam matory/autoimmune diseases.