REGULATION OF ADRENOCORTICAL FUNCTION BY TUMOR NECROSIS FACTOR-α

SILVINA R VILLAR1,*,AILIN LEPLETIER3, EDUARDO ROGGERO1,2, WILSON SAVINO3, ANA ROSA PÉREZ1, OSCAR BOTTASSO1.

Puebla

Congreso; V Iberoamerica Congress on Neuroinmmunomodulation and I Mexican Congress on Neuroimmunoencdocrinology; 2013

International Society for NeuroInmmunoModulatio (ISNIM)

It has been established that the stimulation of the adrenal gland by immune challenges occurs via the HPA axis activation, but there is some 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 Trypanosomacruziacute infection, systemic cytokines are involved in the activation of HPA axis and increased GCs release. Moreover, T. cruzi-infected TNF-R1 knockout (TNF-R1-/-) mice showed an exacerbated synthesis of GCs.Given that cytokines like TNF-αmight influence the release of GCs via direct adrenal effects, we explored the intra-adrenal mechanisms involved in the synthesis of GCs during T.cruzi infection, particularly the role of TNF-α. Infected (Tc) wild type (WT) and TNF-R1-/- mice undergoing acute infection displayed an evident adrenal hyperplasia together with an increased release of GCs. Notably, systemic ACTH levels remained unchanged in both infected groupscompared with uninfected controls, suggesting some degree of ACTH-independence of GCs synthesis. Infection in WT mice resulted in an increased adrenal expression of TNF-R1. Intra adrenal expression of TNF-α was increased in both infected groups. The accumulation of mRNAs for steroidogenicenzimes(StAR, CYP11A1, CYP11B1, 11β-HSD1, 11β-HSD2) were significantly increased in bothinfected groups of mice, being significantly augmented in Tc-TNF-R1-/-compared to Tc-WT, which also had remarkably increased levels of GCs. It follows that local inflammatory agents activate anintrinsically regulated local signaling circuit likely to influencethe adrenals? response to immune stress that may helpexplain the dissociation between plasma levels of ACTH andcorticosteroids.TNF-α emerges as a potent modulator of steroidogenesis in adrenocortical cells during T. cruzi infection.