title: Tumor necrosis factor-α regulates glucocorticoid synthesis in the adrenal glands of Trypanosoma cruzi acutely-infected mice. the role of TNF-R1.
abstract: Adrenal steroidogenesis is under a complex regulation involving extrinsic and intrinsic adrenal factors. TNF-α 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-α 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(-/-) 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-α 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-κB 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-α emerges as a potent modulator of steroidogenesis in adrenocortical cells during T. cruzi 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 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.
authors.affiliation: Instituto de Inmunología, Facultad de Ciencias Médicas, Universidad Nacional de Rosario, Rosario, Argentina. svillar@conicet.gov.ar
authors.forename: Silvina R
authors.initials: SR
authors.lastname: Villar
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Ronco
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernández Bussy
authors.forename: Eduardo
authors.initials: E
authors.lastname: Roggero
authors.forename: Ailin
authors.initials: A
authors.lastname: Lepletier
authors.forename: Romina
authors.initials: R
authors.lastname: Manarin
authors.forename: Wilson
authors.initials: W
authors.lastname: Savino
authors.forename: Ana Rosa
authors.initials: AR
authors.lastname: Pérez
authors.forename: Oscar
authors.initials: O
authors.lastname: Bottasso
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D014355:Chagas Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology*; D003345:Corticosterone / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005938:Glucocorticoids / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014349:Trypanosoma cruzi; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D020928:Mitogen-Activated Protein Kinases; D003345:Corticosterone