Tumor Necrosis Factor-alpha regulates glucocorticoid synthesis in the adrenal glands of Trypanosoma cruzi acutely-infected mice. The role of TNF-R1.

VILLAR S, RONCO MT, FERNÁNDEZ BUSSY R, ROGGERO E, LEPLETIER A, MANARIN R, WILSON S, PEREZ AR, BOTTASSO O

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013 vol. 22 p. 14 - 22

1932-6203

Adrenal steroidogenesis is under a complex regulation involving extrinsic and intrinsic adrenal factors. TNF-alpha is an inflammatory cytokine produced in response to tissue injury and several other stimuli. We have previously demonstrated that TNF-R1-/- (TNF-R1 knockout) mice have a dysregulated synthesis of corticosterone during Trypanosoma cruzi (Tc) acute infection. Since TNF-alpha may influence corticosterone production, not only through the hypothalamus-pituitary axis, but also at the adrenal level, we investigated herein the role of this cytokine upon the adrenal glucocorticoid production. Wild type and TNF-R1-/- mice undergoing acute Tc infection, presented adrenal hyperplasia together with increased corticosterone levels. Notably, ACTH plasma concentrations remained unchanged in Tc-WT and Tc-TNF-R1-/- compared with non-infected mice, suggesting some degree of ACTH-independence of corticosterone synthesis. TNF-alpha expression was increased within the adrenal gland from both infected mouse groups, with Tc-WT mice showing an augmented TNF-R1 expression. Tc-WT mice showed increased levels of P-p38 and P-ERK compared to non-infected WT animals, whereas Tc-TNF-R1-/- mice had increased p38, ERK and JNK phosphorylation respect to Tc-WT mice. Strikingly, adrenal NF-kB and AP-1 activation during infection was blunted in Tc-TNF-R1-/- mice. The accumulation of mRNAs for steroidogenic acute regulatory protein and cytochrome P450 were significantly increased in both Tc-WT and Tc-TNF-R1-/- mice; being much more augmented in the latter group, which also had remarkably increased corticosterone levels. TNF-alpha emerges as a potent modulator of steroidogenesis in adrenocortical cells during Tc infection in which MAPK pathways, NF-κB and AP-1 seem to play a role in the adrenal synthesis of pro-inflammatory cytokines and enzymes involved in the sysnthesis of corticosteroids.. Accordingly, these results unravel the existence of an immunoadrenal interaction involved in the pathogenesis of murine Chagas disease.