EVIDENCE IN FAVOR OF AN ALTERNATIVE GLUCOCORTICOID SYNTHESIS PATHWAY DURING ACUTE EXPERIMENTAL CHAGAS DISEASE

ESDRAS DA SILVA BARBOSA OLIVEIRA; ROCIO DEL VALLE FERNANDEZ; ANA ROSA PÉREZ; EDUARDO ANGEL ROGGERO; VINICIUS FRIAS CARVALHO; SILVINA RAQUEL VILLAR ; FLORENCIA BELEN GONZALEZ; OSCAR BOTTASSO

Frotiers Endocrinology

Frontiers

Lugar: Lausanne; Año: 2019 vol. 10 p. 1 - 9

It is well established that infectious stress activates the hypothalamus-pituitary-adrenal axis leading to the productionof pituitary adrenocorticotropin (ACTH) and adrenal glucocorticoids (GC). Usually, GC synthesis is mediated by PKA signaling pathway triggered by ACTH. We previously demonstrated that acute murine Chagas disease courses with amarked increase of GC, with some data suggesting that GC synthesis may be ACTH-dissociated in the late phase of this parasitic infection. Alternative pathways of GC synthesis have been reported in sepsis or mental diseases, inwhich interleukin (IL)-1β, prostaglandin E2 (PGE2) and/or cAMP activated guanine nucleotide exchange factor 2 (EPAC2) are likely to play a role in this regard. Accordingly, we have searched for the existence of an ACTH-independent pathway in an experimental model of a mayor parasitic disease like Chagas disease, in addition to characterizing potential alternative pathways of GC synthesis. To this end, C57BL/6 male mice were infected with T. cruzi (Tc), and evaluated throughout the acute phase for several parameters, including the kinetic of GC and ACTH release, the adrenal level of MC2R (ACTH receptor) expression, the p-PKA/PKA ratio as ACTH-dependentmechanism of signal transduction, as well as adrenal expression of IL-1β and its receptor, EPAC2 and PGE2 synthase. Our results reveal the existence of two phases involved in GC synthesis during Tc-infection in mice, an initialone dealing with the well-known ACTH-dependent pathway, followed by a further ACTH-hyporesponsive phase. Furthermore, inflamed adrenal microenvironment may tune the production of intracellular mediators that also operateupon GC synthesis, like PGE2 synthase and EPAC2, as emerging driving-forces for GC production in the advancedcourse of Tc infection. In essence, GC production seems to be associated with a biphasic action of PGE2, suggestingthat the effect of PGE2/cAMP in the ACTH-independent second phase may be mediated by EPAC2.