Intrapituitary cytokines in Cushing's disease: do they play a role?

A large body of in vitro evidence shows that cytokines influence the hypothalamic-pituitary-adrenal axis both in physiological conditions and in Cushing's disease (CD). In order to study in vivo the role of intrapituitary cytokines in CD, we assayed two cytokines known for their action on the pituitary, i.e. interleukin-1 beta (IL-1β) and interleukin-6 (IL-6), and also soluble interleukin-6 receptor (sIL-6R), important for the neural activities of IL-6, in a carefully selected sample of subjects affected by CD undergoing bilateral inferior petrosal sinus sampling. Similarly to ACTH, all cytokines basally showed a higher concentration in the ipsilateral sinus compared to the controlateral one and to that of peripheral blood; after CRH infusion, both ipsilaterally and controlaterally, IL-6 and sIL-6R values increased compared to basal ones, while IL-1β increased significantly up to 5 min after CRH and then decreased significantly compared to basal values in subsequent measurements; peripherically no significant variations in the cytokines were observed after CRH. Again similarly to ACTH, the three cytokines presented a higher increase ipsilaterally than controlaterally; moreover all three interleukins in the ipsilateral sinuses showed positive and significant correlations between their basal value and that of basal ACTH. These findings allow us to hypothesize that the central production of IL-1β and IL-6 could be involved in ACTH hypersecretion which occurs in CD: more specifically, we hypothesize that these cytokines are produced directly by the corticotroph adenoma and have the task of enhancing tumoral secretion of ACTH with an autocrine-paracrine mechanism.