PhD

dissertationThe neuroendocrine system regulates a variety of lymphoid cell activities through the actions of steroid hormones, including dehydroepiandrosterone (DHEA) and the glucocorticoids (GCS). This provides a linkage between the neuroendocrine and immune systems through the autocrine, paracrine, and endocrine acting substances that are produced. The studies in this thesis describe the mechanisms utilized by the lymphoid system to microenvironmentally control the immunomodulatory actions of DHEA and GCS in vivo. In the circulation, DHEA exists predominantly as the hydrophilic sulfated derivative dehydroepiandrosterone sulfate (DHEAS). The enzyme DHEAS sulfatase generates DHEA through the hydrolysis of the 3-beta-sulfate group. The DHEA that is formed from this enzymatic process is hydrophobic and effectively diffuses across cellular membranes. High levels of DHEAS sulfatase activity were observed within lymphoid organs, and predominantly associates with the macrophage. Stimulation of macrophages with a variety of microbial substances markedly inhibited the conversion of DHEAS to DHEA. Inhibition of enzyme activity was determined to be mediated by the actions of the macrophage synthesized cytokines TNF-alpha and IFN-alpha. Lymphoid organs were found to possess substantial levels of the enzyme 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD). This enzyme interconverts the biologically active 11-hydroxy GCS to their biologically inactive 11-keto metabolites. Enzyme activity was found to vary within distinct lymphoid organs and associate with the immobile stromal elements. Physical and enzymological properties of the 11-beta-HSD activity present within lymphoid organs differed from the properties described for the two recently cloned and characterized 11-beta-HSD1 and 11-beta-HSD2 isoforms, suggesting the existence within these tissues of a novel 11-beta-HSD isoform. Inhibition of lymphoid organ 11-beta-HSD activity in vivo resulted in altered immune effector functions. This included a reduction in the production of activation inducible pro-inflammatory cytokines plus a depression in cell mediated immune responses. Similar effects are observed following the exogenous administration of GCS. These findings indicate that 11-beta-HSD within lymphoid organs and other tissues control the capacity of the GCS to function as immunomodulatory substances