Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis.
Interleukin (IL)-6 is a potent activator of the human hypothalamicpituitary-adrenal axis. After chronic administration of IL-6 in humans, there is a substantial elevation of cortisol, whereas ACTH levels are blunted. Thus, we investigated whether IL-6 and/or the IL-6 receptor (IL-6R) are expressed in the human adrenal gland and whether IL-6 could cause the release of steroid hormones by a direct action on adrenal cells in primary culture. The expression of IL-6 and IL-6R was investigated with RT-PCR and immunohistochemistry, and the effects on human adrenal steroidogenesis were tested with IL-6 in vitro. To avoid effects mediated by macrophages, we depleted adrenal primary cultures from macrophages using specific mouse antihuman CD68 and sheep antimouse IgG conjugated magnetic beads. The results showed that 1): IL-6 and IL-6R are expressed in adrenal cell cultures, including all cell types and those depleted of macrophages; 2) IL-6R is mainly expressed in the zona reticularis and the inner zona fasciculata; positive signals from the zona glomerulosa and the medulla occurred in single cells; and 3) IL-6 regulates adrenal synthesis of mineralocorticoids, glucocorticoids, and androgens in vitro, dependent on time and dose, in the absence of macrophages. After 24 h, aldosterone secretion increased to 172 +/- 28% SEM, cortisol to 177 +/- 27% SEM, and dehydroepiandrosterone to 153 +/- 20% SEM of basal secretion. These findings, in combination with previous investigations, suggest that IL-6 exerts its acute action via the hypothalamus and the pituitary. In the adrenal gland, however, IL-6 seems to be a long-term regulator of stress response, integrating the responses of all cortical zones to stimuli from the immune and endocrine system.
Päth
G
G
Department of Internal Medicine III, University of Leipzig, Germany.
Bornstein
S R
SR
Ehrhart-Bornstein
M
M
Scherbaum
W A
WA
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000368:Aged; D000450:Aldosterone / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D013997:Time Factors
D015703:Antigens, CD; D015850:Interleukin-6; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D003687:Dehydroepiandrosterone; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone