IMMUNOREGULATION BY CORTICOTROPIN-RELEASING HORMONE

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The broad, long-term objective of this proposal is to determine how the neuropeptide corticotropin releasing hormone (CRH) modulates the activity of the immune system under both normal and pathologic conditions. CRH is the major central nervous system regulator of the neuroendocrine, autonomic, and behavioral responses to stress. It is also found in peripheral nerves and in several organs. An immunoregulatory role is suggested by its ability to influence immunocompetent cells in vitro, including its ability to preferentially stimulate mesenteric lymph node and Peyer's patch B-lymphocyte proliferation. Its activity on gut associated lymphoid tissue suggests that CRH containing neurons in gastrointestinal (GI) mucosa are involved in modulation of secretory immunity in the GI tract. The specific aims are to 1.) characterize CRH receptors in the immune system and determine which cells in the immune system express CRH receptors, 2) determine how CRH effects cellular function in the immune system, and 3.) determine whether normal or transformed cells in the immune system produce CRH. The experimental design will use an integrated approach which correlates CRH receptor characterization with the effect of CRH on specific cell functions in the immune system. CRH receptor characterization and localization on enriched populations of lymphocytes from rat lymphoid organs will use radioligand binding studies, fluorescence activated cell sorter analysis with fluoresceinated CRH analogs, and affinity labelling. Functional studies will assess the effect of CRH on second messenger systems, and on the effect of CRH on in vitro measures of B and T lymphocyte function, including immunoglobulin secretion and cell mediated cytotoxicity. Production of CRH by normal and transformed cells will be assessed by a combination of northern blot and polymerase chain reaction analysis to detect CRH mRNA, and radioimmunoassay to detect CRH peptides. A better understanding of the role of CRH in specific receptor mediated modulation of immune function will provide important information on how peripheral nervous system neuropeptides mediate immune function and inflammation. These studies could have important implications in the diagnosis and treatment of human disease.