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Tumor Necrosis Factor- Regulates Steroidogenesis, Apoptosis, and Cell Viability in the Human Adrenocortical Cell Line NCI-H295R

Department of Pediatrics, Kuopio University and University Hospital, FI-70211 Kuopio, Finland

Address all correspondence and requests for reprints to: Raimo Voutilainen, Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio, Finland. E-mail: Raimo.Voutilainen{at}uku.fi.

TNF- regulates the hypothalamo-pituitary-adrenal axis at several levels. It has been shown to modify adrenal steroidogenesis in many species, and it is supposed to act as an auto/paracrine factor. However, its significance in human adrenocortical function remains unclear. Therefore, we investigated the effect of TNF- on adrenal steroidogenesis, expression of the key steroidogenic genes, apoptosis, and cell viability in the human adrenocortical cell line NCI-H295R. TNF- treatment (1 nM for 48 h) decreased the basal production of cortisol, androstenedione, dehydroepiandrosterone sulfate (DHEAS), and aldosterone (14, 18, 35, and 52%, respectively), and the 8-bromo-cAMP-induced production of cortisol, androstenedione, dehydroepiandrosterone (DHEA), and DHEAS (44, 66, 58, and 48%, respectively). However, when the steroid production data were normalized by the cell number, TNF- increased the basal production of cortisol, androstenedione, DHEA, DHEAS, and aldosterone (137, 121, 165, 73, and 28%, respectively), and the 8-bromo-cAMP-induced production of cortisol, DHEAS, and aldosterone (122, 121, and 256%, respectively). This was accompanied by a parallel increase in the expression of the genes encoding for the steroidogenic acute regulatory protein, 3ß-hydroxysteroid dehydrogenase 2, and 17-hydroxylase/17,20-lyase (74, 200, and 50%, respectively; quantitative real-time RT-PCR analysis). TNF- increased caspase 3/7 activity (an indicator of apoptosis) and decreased cell viability dose and time dependently. The effect of TNF- on apoptosis was neutralized by a monoclonal TNF- antibody. These findings indicate that TNF- is a potent regulator of steroidogenesis and cell viability in adrenocortical cells. TNF- may have physiological and/or pathophysiological significance as an endocrine and/or paracrine/autocrine regulator of adrenocortical function.

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