Edward C. Miner and Dr. Allan M. Judd, Zoology
The adrenal cortex releases aldosterone, cortisol, and dehydroepiandrosterone (DHEA) into the blood stream. The regulation of aldosterone and cortisol release by the adrenal gland is well studied. In contrast, little is known about the regulation of DHEA secretion. Since low plasma levels of DHEA are associated with the aging process, rheumatoid arthritis, and disease progression in HIV-infected individuals, it is medically significant to determine the mechanism of DHEA release from the adrenal gland.
Cytokines, also called immunocytokines or immunotransmitters, are soluble proteins and peptides that act as humoral regulators at very small concentrations. They are similar to classical hormones, except that while classical hormones normally act on a specific target cell group, cytokines can act on a systemic level. Under normal and pathological conditions, they modulate the functional activities of individual cells and tissues. Cytokines also mediate interactions between cells directly and regulate processes taking place in the extracellular environment.
Since cytokines are produced in several endocrine tissues, including the adrenal gland, they may regulate adrenal function. Because the serum and tissue concentrations of cytokines increase during stress and disease, it is important to determine the role of cytokines on DHEA release from the adrenal cortex.
Cells from the zona reticularis layer of bovine adrenal glands were isolated and transferred to culture plates containing cell culture medium. The plates were then incubated for 5-6 days in an atmosphere of 5% carbon dioxide and 95% air. On the day of an experiment the old medium was removed and replaced with a medium of serum-free cell-culture medium containing various pharmacological test agents. The adrenal cells were then incubated with these agents for 24 hours, and the medium was removed from the cells. Then the cell medium was stored frozen, and assayed for DHEA. The amount of DHEA secreted by the cells was determined by radioimmunoassay using commercially available antibodies and radioactive DHEA. The test agents utilized in this study included adrenocorticotropin hormone (ACTH), an important stimulator of DHEA release, and the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-I) and interleukin-6 (IL-6).
As the graphs on the following page show, a dramatic reduction in DHEA secretion was seen in cells treated with any of the three cytokines in this study (TNF, IL-1, or IL-6). This decrease is especially large at concentrations greater than 10 pg/ml and is observed in both the presence and absence of ACTH. TNF is shown to decrease DHEA secretion by a factor of 6, IL- 1 by a factor of 3, and and IL-6 by a factor of 2. Since adrenal cells are known to secrete each of these cytokines, these results suggest that these cells may use cytokines to regulate DHEA secretion in an autocrine/paracrine manner.