Adrenal corticosteroids exert well documented modulatory influences upon numerous cell types that comprise the immune system. At low concentrations, corticosterone has been found to enhance immunogenesis while at elevated concentrations, this steroid is immunosuppressive. Recent evidence suggests that this family of steroids constitutes an integral part of a mechanism by which a state of homeostatic balance is maintained within the immune system. Furthermore, signals originating from within the immune compartment appear to regulate this immunomodulatory axis. This signal is present within a partially purified thymosin preparation designated Thymosin fraction 5 (TSN-5). Preliminary studies have revealed that TSN-5 can stimulate beta-endorphin, ACTH and cortisol release in monkeys and corticosterone release in mice and rats. The site of this stimulation is the CNS-pituitary axis since isolated adrenal fasciculata cells fail to synthesize C-AMP or corticosterone in response to various thymosin peptides. Furthermore, injection of certain thymosin peptides directly into the brain has been found to result in corticogenesis using considerably lower concentrations than when the same peptides were injected intraperiotoneally. The proposed experiments have been designed to identify the biologically active components of TSN-5 that is responsible for producing these effects. This will be accomplished by evaluating progressively more purified fragments of TSN-5 following elution by HPLC in both in vivo and in vitro protocols. This will include the further characterization of the dose and temporal kinetics of thymosin activation of the hypothalamic-pituitary-adrenal axis following both systemic and intracerebral administration. Discrete, subcortical brain nuclei will be targeted in order to identify the site of action within the CNS. A single or double chamber superfusion system will be used to test for direct effects of the thymosin preparations upon isolated hypothalamic and/or pituitary tissue. Pituitary cells will be cultured as monolayers and treated directly with the various preparations. Corticosteroid influences upon the immune system are well documented, but poorly characterized. The studies will provide a better understanding of the regulation of these immunomodulatory steroids by signals originating from within the immune system.
