EPAC2 AND PROSTAGLANDIN-E2 SINTASA INVOLVEMENT IN GLUCOCORTICOID STEROIDOGENESIS DURING EXPERIMENTAL TRYPANOSOMA CRUZI INFECTION

ESDRAS DA SILVA OLIVEIRA BARBOSA, EDUARDO ROGGERO, ROCÍO DEL V FERNÁNDEZ, FLORENCIA BELÉN GONZALEZ, OSCAR BOTTASSO, ANA ROSA PÉREZ, SILVINA RAQUEL VILLAR

Mar del Plata

Congreso; Reunión SAIC-SAI-SAFIS. Mar del Plata 14 al 17 de noviembre 2018; 2018

The hypothalamic?pituitary?adrenal (HPA) axis is a dynamic systemthat regulates glucocorticoid (GC) synthesis in the adrenal glands.The classic GC-releasing reflex is mainly mediated by ACTH. Manykey factors, such as cytokines, prostaglandin-E2 (PGE2) and Epac2have been identified as intra-adrenal enhancers of steroideogenesisindependently of systemic ACTH levels. However, little is knownabout how these factors collectively influence GC synthesis duringTrypanosoma cruzi (Tc) infection.Previous studies in Tc-infected mice showed after 14 days post-infection(dpi) increased circulating levels of GC, while ACTH remainsunchanged. At the same time, intra-adrenal expression of pro-inflammatorycytokines is augmented.In this study, we decided to evaluate the ACTH-dependent and independentpathways of GC synthesis during Tc infection. Thus, wedetermined at different dpi the expression of PKA-p/PKA (as a measureof ACTH-dependent pathway activation) and also PGE2-synthase(PGE2-S) and Epac2 as ACTH-independent modulators ofadrenal steroideogenesis. C57BL/6 mice were infected with Tc orinoculated with saline (Co). Data are showed as mean±SEM (n=3-5/day/group). Assessments were made between 10 to 21 dpi. ThePKA-p/PKA ratio was increased only at 11 dpi [Western blot, PKA-p/PKA: Co=1±01; Tc(10dpi)=1.1±0.1; Tc(11dpi)=2.4±0.7*; Tc(13dpi)=1.0±0.2; Tc(14dpi)=1.1±0.2; Tc(16dpi)=0.8±0.1; *p<0,05 vs Co].Tc mice displayed significantly intra-adrenal elevation of PGE2-Safter 11 dpi [RT-qPCR, PGE2-S: Co=7.8±1.2; Tc(10dpi)=13.1±5.4;Tc(11dpi)=29.1±14.5*; Tc(13dpi)=22.4±1.9*; Tc(14dpi)=31.7±6.6*;Tc(19dpi)=47.7±17.7*; *p<0,05 vs Co]. Moreover, Epac2 increasedafter 14dpi (RT-qPCR and Western, p<0,05 vs Co), decreasing after16dpi. In parallel, no statistical differences were observed regardingIL-1R expression (Western blot and RT-qPCR).These results suggested that Tc infection activates both steroidogenicpathways, resulting in a remarkably increased GC production.Also, our results suggest that early in the course of infection, GCsecretion may be triggered by the ACTH-mediated response, but inthe late phase of acute infection, GC secretion may be sustained byother factors including PGE2 and Epac2.