Tumor Necrosis Factor as a Potent Inhibitor of Adrenocorticotropin-Induced Cortisol Production and Steroidogenic P450 Enzyme Gene Expression in Cultured Human Fetal Adrenal Cells*

Abstract

We have previously demonstrated that tumor necrosis factor alpha (TNF-alpha), a multifunctional cytokine mainly produced by activated monocytes, inhibits the ACTH-induced production of cortisol in cultures of human fetal adrenals. To clarify the molecular basis of this suppression, we investigated the effect of recombinant TNF-alpha (rTNF-alpha) on the messenger RNAs (mRNAs) for adrenal cytochrome P450 oxidases, P450scc (cholesterol side-chain cleavage enzyme/20.22-desmolase), P450c11 (11 beta-hydroxylase/18-hydroxylase/18-methyl oxidase), P450c17 (17 alpha-hydroxylase/17,20-lyase), and P450c21 (21-hydroxylase). Northern and dot blot experiments showed that 36 h incubation of primary cultures of human fetal adrenals with ACTH (200 ng/ml) increased the levels of all P450 enzymes severalfold. Preincubation of the cultures with rTNF-alpha at concentrations ranging from 0.1-100 ng/ml produced a dose-dependent inhibition of the ACTH-induced accumulation of all P450 mRNAs. The decrease in the expression of genes for steroidogenic enzymes was accompanied by a similar decrease in the production of cortisol but not in that of dehydroepiandrosterone sulphate nor androstenedione. Neither the basal expression of P450 enzymes nor the basal secretion of the steroids was significantly altered by 10 ng/ml of rTNF-alpha. rTNF-alpha did not affect the level of actin mRNA, the cell viability, nor the cell number. All the effects brought about by rTNF-alpha could be neutralized by addition of monoclonal anti-TNF-alpha antibody. These results show that TNF-alpha suppresses the synthesis of cortisol and shifts the steroid secretory pattern towards androgen production at least partly by suppressing the accumulation of mRNAs for adrenal cytochrome P450 oxidases.

Assessing adrenal status in patients before and immediately after coronary artery bypass graft surgery

“…A number of mechanisms may be responsible. TNFa reduces adrenal cortisol synthesis by reducing the sensitivity of adrenal receptors to ACTH resulting in a blunted response to cosyntropin and high ACTH levels with relatively low cortisol levels in the setting of acute illness (35). In addition, corticostatins or defensins produced by cells, such as macrophages and neutrophils, and which may proliferate in a systemic inflammatory response, inhibit the steroidogenic activity of ACTH.…”

Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM)

“…The presence of TNF and of its receptors within the adrenal glands suggests that this cytokine plays a role in adrenal function, even though experiments found variably stimulatory [43,44] or inhibitory [45,46] effects of TNF on steroidogenesis. Likewise, IL-1 and its receptor are also produced in the adrenal glands and contribute to steroidogenesis at least partly by regulating prostaglandin pathways [47].…”

Leukemia inhibitory factor as a regulator of steroidogenesis in human NCI-H295R adrenocortical cells

“…However, there are dozens of additional hormones, neuropeptides, and cytokines involved in this regulation. Proinflammatory cytokines TNF (Jäättelä et al 1990, 1991, Ilvesmäki et al 1993, Voutilainen 1998, Judd et al 2000, Mikhaylova et al 2007), IL6 , Judd et al 2000, and IL1B have been shown to modulate bovine, murine, and human adrenal steroidogenesis.…”