Regulation of adrenocortical function by Tumor Necrosis Factor-alpha

VILLAR S; LEPLETIER A; ROGGERO E; SAVINO W; PEREZ A; BOTTASSO O

Pueba

Congreso; IV Iberoamerican Congress on Neuroimmunomodulation and I Mexican Congress on Neuroimmunoendocrinology. Puebla-México Oct. 29th-Nov.1st, 2013; Pp76.; 2013

ISNIM

It has been established that the stimulation of the adrenal gland by immune challenges occur via HPA axis activation, but also there is evidence that inflammatory mediators may influence the release of glucocorticoids (GCs) through direct effects on the adrenal cells. The mechanisms underlying these effects are unknown. We have previously demonstrated that during Trypanosoma cruzi acute infection, systemic cytokines are involved in the activation of HPA axis and increased GCs release. Moreover, T. cruzi-infected TNF-R1 knockout (TNFR1-/-) mice showed an exacerbated synthesis of GCs. Taking into account that cytokines like TNF-α might influence the release of GCs via direct effects on the adrenal gland, we decided explore the intra-adrenal mechanisms involved in the synthesis of GCs during T.cruzi infection, particularly the role of TNF-a. Infected (Tc) wild type (WT) and TNF-R1-/- mice undergoing acute infection displayed an evident adrenal hyperplasia together with an increased release of GCs, but notably, systemic ACTH levels remained unchanged in both infected groups compared with uninfected controls, suggesting some degree of ACTH-independence of GCs synthesis. Infection in WT mice induces in adrenals an increase expression of TNF-R1. Intra adrenal expression of TNF-a was increased in both infected groups. The accumulation of mRNAs for steroidogenic enzimes (StAR, CYP11A1, CYP11B1, 11B-HSD1, 11B-HSD2) were significantly increased in both infected groups of mice, being significantly augmented in Tc-TNFR1-/- compared to Tc-WT, which also had remarkably increased levels of GCs. These data demonstrate a mechanism by which local inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids. TNF-a emerges as a potent modulator of steroidogenesis in adrenocortical cells during T. cruzi infection.