RESUMO
Inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) regulate the activity of the hypothalamo-pituitary-adrenal (HPA) axis at several levels. Although hypothalamic CRH secretion may be the primary mechanism by which these cytokines activate the HPA axis, IL-1 expression is increased within the adrenal glands in models for systemic inflammation, and IL-1 may augment adrenal glucocorticoid production. Our aim was to investigate the direct effects of IL-1α and IL-1ß on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI-H295R cell line as a model. mRNAs encoding receptors for IL-1, TNF-α, and leukemia inhibitory factor (LIF) were detectable in the cell line (Affymetrix microarray analysis). Both IL-1α and IL-1ß increased cortisol, androstenedione, dehydroepiandrosterone and dehydroepiandrosterone sulfate production, and the accumulation of mRNAs for steroidogenic acute regulatory protein (STAR), 17α-hydroxylase/17,20-lyase (CYP17A1) and 3ß-hydroxysteroid dehydrogenase 2 (HSD3B2) in these cells (P<0.05 for all). Both ILs augmented TNF-α- and LIF-induced STAR and CYP17A1 mRNA accumulation, and TNF-α-induced cortisol production (P<0.05 for all). Both ILs also increased the apoptotic index of the cells (P<0.05), which was efficiently neutralized by their specific antibodies. The IL-induced changes in the STAR, HSD3B2, and CYP17A1 protein levels were not as evident as those in the respective mRNA levels. In conclusion, the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production, and thus explain the observed discrepancy between the cortisol and ACTH concentrations sometimes seen in sepsis and chronic inflammatory states.