We have characterized the actions on the hypothalamic-pituitary axis of a number of cytokines which include interleukin-1 (IL-1), IL-2, lL-6, tumor necrosis factor (TNFalpha), gamma-interferon and thymosin alpha1. The hypothesis is that the pattern of hypothalamic-pituitary hormone release that is brought about by infection is induced by these various cytokines which are released as a result of the stimulation of their production and release by bacterial and viral endotoxins. All of these cytokines appear to have actions, both on the hypothalamus and the anterior pituitary gland with the rapid effects mediated via hypothalamic action and the slower effects mediated by combined hypothalamic-pituitary actions. Because excessive release and actions of cytokines are very damaging in a number of diseases, agents which block their action may have great therapeutic value. Consequently, this research is aimed at identifying the site of action, the molecular mechanism of action and pathophysiologic significance of cytokines thought to play a role in the development of the CNS and hypothalamic-pituitary pathology in AIDS with the view that agents which can block the action of these cytokines might be of value in the treatment of patients with AIDS, and other conditions such as toxic shock associated with excess production and action of cytokines. It is the purpose of this grant to determine the cell type on which these various cytokines are acting both in the hypothalamus and in the pituitary to modify the release of hypothalamic and pituitary hormones and their molecular mechanism of action at both hypothalamic and pituitary sites. These anticytokine agents might also be valuable, particularly in acute conditions such as toxic shock associated with excess production and action of cytokines.
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