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Lymphocytes Stimulate Dehydroepiandrosterone Production through Direct Cellular Contact with Adrenal Zona Reticularis Cells: A Novel Mechanism of Immune-Endocrine Interaction¹

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (G.W.W., G.P.C., S.R.B.), Bethesda, Maryland 20892; Diabetes Research Institute, University of Dusseldorf (W.A.S.), Dusseldorf 40001, Germany; and the Department of Internal Medicine, University of Leipzig (T.L., S.S., R.P., H.-D.S., S.R.B.), Leipzig 04103, Germany

Address all correspondence and requests for reprints to: Dr. G. W. Wolkersdörfer, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892. E-mail: WolkersdoerferG{at}netscape.net

Adrenal androgen production was reduced by 80% in patients receiving T lymphocyte-suppressive medications compared to that in age-matched controls. In vitro, however, neither tacrolimus nor cyclosporin A reduced dehydroepiandrosterone (DHEA) release by adrenocortical cells. Therefore, we examined the potential role of lymphocytes in adrenal androgen production, using cocultures of human T lymphocytes and adrenocortical primary or transformed cells. Cocultures led to a 4-fold elevation of DHEA levels (490.4 ± 94.8% over basal), which was greater than the increase observed after the addition of maximal concentrations of ACTH (117.4 ± 14.8%). Separation of cells by semipermeable membranes abolished this effect, and transfer of leukocyte-conditioned medium had little androgen-stimulating effect. These data suggested that the observed stimulation of androgen secretion required cell contact rather than soluble paracrine factor(s). Furthermore, we examined human adrenal glands for the presence of T lymphocytes and contact between these cells and steroid-secreting cells of the zona reticularis. Indeed, T lymphocytes expressing CD4 and CD8 antigens were present within human adrenal zona reticularis by immunohistochemical subtyping. Electron microscopic analyses demonstrated direct cell-cell contact between T lymphocytes and adrenocortical cells in situ. This study provides evidence for a novel mechanism of immune-endocrine interactions of direct T lymphocyte-adrenocortical cell contact-mediated stimulation of adrenal androgen secretion.

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