Tumor Necrosis Factor-a Regulates Glucocorticoid Synthesis in the Adrenal Glands of Trypanosoma cruzi Acutely-Infected Mice . The Role of TNF-R 1

Adrenal steroidogenesis is under a complex regulation involving extrinsic and intrinsic adrenal factors. TNF-a is an inflammatory cytokine produced in response to tissue injury and several other stimuli. We have previously demonstrated that TNF-R1 knockout (TNF-R1) mice have a dysregulated synthesis of glucocorticoids (GCs) during Trypanosoma cruzi acute infection. Since TNF-a may influence GCs production, not only through the hypothalamus-pituitary axis, but also at the adrenal level, we now investigated the role of this cytokine on the adrenal GCs production. Wild type (WT) and TNF-R1 2 mice undergoing acute infection (Tc-WT and Tc-TNF-R1 groups), displayed adrenal hyperplasia together with increased GCs levels. Notably, systemic ACTH remained unchanged in Tc-WT and Tc-TNF-R1 compared with uninfected mice, suggesting some degree of ACTH-independence of GCs synthesis. TNF-a 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 uninfected WT animals, whereas Tc-TNF-R1 mice had increased p38 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 GCs levels. TNF-a emerges as a potent modulator of steroidogenesis in adrenocortical cells during T. cruzi infection in which MAPK pathways, NF-kB and AP-1 seem to play a role in the adrenal synthesis of pro-inflammatory cytokines and enzymes regulating GCs synthesis. These results suggest the existence of an intrinsic immune-adrenal interaction involved in the dysregulated synthesis of GCs during murine Chagas disease. Citation: Villar SR, Ronco MT, Fernández Bussy R, Roggero E, Lepletier A, et al. (2013) Tumor Necrosis Factor-a Regulates Glucocorticoid Synthesis in the Adrenal Glands of Trypanosoma cruzi Acutely-Infected Mice. The Role of TNF-R1. PLoS ONE 8(5): e63814. doi:10.1371/journal.pone. 0063814 Editor: Anna Carla Goldberg, Albert Einstein Institute for Research and Education, Brazil Received December 19, 2012; Accepted April 7, 2013; Published May 22, 2013 Copyright: 2013 Villar et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: S.R. V. , A.R. P., M.T. R. and O.A. B. are members of National Council Research (CONICET). Support for this study was provided by SCYT-UNR (1MED 372) and Agencia Nacional de Promoción Cientı́fica y Tecnológica (ANPCyT, PICT 2008-0980), AmSud-Pasteur Network, as well as CNPq and Faperj (Brazil). The funders had no role in study design, data collection and analysis, decision to publish or preparation the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: svillar@conicet.gov. ar