It is the purpose of this application to evaluate the role of the various monokines in inducing the hypothalamic-pituitary response to infection. We will determine effects of interleukin 1 and interleukin 2 in altering hypothalamic pituitary function and determine whether the effects are mediated directly on the hypothalamus or on the pituitary. We have already performed preliminary experiments with interleukin 1 which indicate that it has a profound effect on the release of GH, TSH and PRL as well as its known capability to stimulate ACTH secretion. We will evaluate the effects of interleukin 2, the newly discovered cachectin, and other monokines as they are obtainable in highly purified or synthetic form, if the actions are mediated via the hypothalamus we will determine whether these are direct actions on the releasing factor neurons or interneurons are involved which then affect the releasing factor neurons via synaptic transmission. We will evaluate the effects on hypothalamic function both in vivo and in vitro and determine which hypothalamic peptide(s) are released. Essentially of particular monokines in bringing about the pattern of release of hypothalamic peptides in infection will be determined by the use developed. The mechanism of the releasing action in the hypothalamus will be investigated by determining the effects of the monokines on the metabolism will be investigated by determining the effects of the monokines on the metabolism of arachidonic acid and by use of suitable antagonists to the active agents in these pathways. Possible direct effects on the pituitary will be evaluated using in vitro incubation of hemipituitaries and dispersed anterior pituitary cells in static and perifusion systems. When such effects are found the mechanism of action will be evaluated. Interactions of the monokines with the various releasing and inhibiting hormones will also be evaluated by incubation of pituitary cells with the monokines in the presence or absence of various doses of these factors. It is hoped that these studies will give a clear understanding of the pathogenesis of the endocrine changes which occur in infectious diseases and that this knowledge may be relevant to understanding of the pathogenesis of AIDS which may in turn be helpful in designing appropriate therapeutic approaches.
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