The Immunoregulatory Actions of DHEA in Tuberculosis, A Tool for Therapeutic Intervention?

Dehydroepiandrosterone (DHEA) is an androgen synthesized by the adrenal cortex, which is an intermediary in the biosynthesis of sex hormones, such as testosterone and estradiol. DHEA mostly circulates as a conjugated ester, in the form of sulfate (DHEA-S). There exist several endogenous factors able to influence its synthesis, the most common ones being the corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), growth factors, and proinflammatory cytokines, among others. Like other steroid hormones, DHEA, can alter the functioning of immune cells and therefore the course of diseases exhibiting an immune-inflammatory component, mostly from autoimmune or infectious nature. We herein review the role played by DHEA during a major infectious disease like tuberculosis (TB). Data recorded from TB patients, mouse models, or in vitro studies show that DHEA is likely to be implied in better disease control. This provides a stimulating background for carrying out clinical studies aimed at assessing the usefulness of DHEA as an adjuvant in TB patients.Fil: Bongiovanni, Bettina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Díaz, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Santucci, Natalia Estefanía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: D'attilio, Luciano David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Hernández Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Bay, Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentin

Increased frequency of CD4+ CD25+ FoxP3+ T regulatory cells in pulmonary Tuberculosis patients undergoing specific treatment and its relationship with their immune-endocrine profile

Tuberculosis (TB) is a major health problem requiring an appropriate cell immune response (IR) to be controlled. Since regulatory T cells (Tregs) are relevant in IR regulation, we analyzed Tregs variations throughout the course of TB treatment and its relationship with changes in immune-endocrine mediators dealing with disease immunopathology. The cohort was composed of 41 adult patients, 20 of them completing treatment and follow-up. Patients were bled at diagnosis (T0) and at 2 (T2), 4 (T4), 6 (T6), and 9 months following treatment initiation. Twenty-four age- and sex-matched healthy controls (HCo) were also included. Tregs (flow cytometry) from TB patients were increased at T0 (versus HCo < 0.05), showing even higher values at T2 (versus T0 < 0.01) and T4 (versus T0 < 0.001). While IL-6, IFN-, TGF- (ELISA), and Cortisol (electrochemiluminescence, EQ) were augmented, DHEA-S (EQ) levels were diminished at T0 with respect to HCo, with cytokines and Cortisol returning to normal values at T9. Tregs correlated positively with IFN- ( = 0.868, < 0.05) at T2 and negatively at T4 ( = −0.795, < 0.05). Lowered levels of proinflammatory cytokines together with an increased frequency of Tregs of patients undergoing specific treatment might reflect a downmodulatory effect of these cells on the accompanying inflammation.Fil: Díaz, Ariana. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico Rosario; ArgentinaFil: Santucci, Natalia Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico Rosario; ArgentinaFil: Bongiovanni, Bettina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico Rosario; ArgentinaFil: D'attilio, Luciano David. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico Rosario; ArgentinaFil: Massoni, Claudia. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Lioi, Susana. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Radcliffe, Stella. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Didoli, Griselda. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; ArgentinaFil: Bottasso, Oscar Adelmo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Cientifico Tecnológico Rosario; ArgentinaFil: Bay, Maria Luisa. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentin

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity

Pulmonary tuberculosis (PTB), caused by Mycobacterium tuberculosis (Mtb), is a major health problem worldwide, further aggravated by the convergence of type 2 diabetes mellitus (DM) which constitutes an important risk factor for TB development. The worse scenario of patients with PTB and DM may be partly related to a more unbalanced defensive response. As such, newly diagnosed PTB patients with DM (TB+DM, n = 11) or not (TB, n = 21), as well as DM (n = 18) patients and pair matched controls (Co, n = 22), were investigated for the circulating immuno-endocrine-metabolic profile (ELISA), along with studies in peripheral blood mononuclear cells (PBMC) analyzing transcript expression (RT-qPCR) of mediators involved in glucocorticoid functionality. Given the hyperglycemic/hypercortisolemic scenario of TB+DM patients, PBMC were also exposed to stress-related cortisol concentrations (0.1 and 1 μM) and supraphysiologic glucose doses (10, 20, and 40 mM) and assessed for the specific response against Mtb stimulation (lymphoproliferation, -thymidine incorporation-, and cytokine production -bead-cytometry). All TB patients displayed increased plasma amounts of cortisol, growth hormone -hGH-, and proinflammatory mediators. In turn, TB+DM showed even higher levels of interferon gamma -IFN-γ- and hGH (vs. TB), or IL-6, C reactive protein, cortisol and hGH (vs. DM). Both DM groups had equally augmented values of IL-10. All TB patients showed decreased dehydroepiandrosterone- sulfate concentrations, even more in TB+DM cases. Leptin was also decreased in both TB cases, particularly in the TB group, revealing a lower body mass index, as well. Unlike PBMC from TB cases showing a decreased relationship between the glucocorticoids receptor (GR) isoforms (GRα/GRβ; functional isoform/negative isoform), cells from TB+DM patients had no changes in this regard, along with an increased expression of 11-beta hydroxysteroid dehydrogenase type-1, the enzyme facilitating intracellular cortisone to cortisol conversion. TB+DM patients also showed an increased Mtb antigen-driven lymphoproliferation. Compared to TB, DM and HCo counterparts, PBMC from TB+DM patients had a biased Th1 response to Mtb stimulation (increased IL-2 and IFN-γ production), even when exposed to inhibitory cortisol doses. TB+DM patients show a more unbalanced immuno-endocrine relationship, respect the non-diabetic counterparts, with a relative deficiency of cortisol immunomodulatory influences, despite their more favorable microenvironment for cortisol-mediated immune effects.Fil: Fernández, Rocío del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Díaz, Ariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bongiovanni, Bettina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Gallucci, Georgina Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bértola, Diego. Universidad Nacional de Rosario; ArgentinaFil: Gardeñez, Walter. Universidad Nacional de Rosario; ArgentinaFil: Lioi, Susana. Hospital Provincial del Centenario; ArgentinaFil: Bertolin, Yésica. Hospital Provincial del Centenario; ArgentinaFil: Galliano, Romina. Hospital Provincial del Centenario; ArgentinaFil: Bay, Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: D'attilio, Luciano David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; Argentin

The Impact of IFN-g; Receptor on SLPI Expression in Active Tuberculosis: Association with Disease Severity

Interferon (IFN)-g displays a critical role in tuberculosis (TB), modulating the innate and adaptive immune responses. Previously, we reported that secretory leukocyte protease inhibitor (SLPI) is a pattern recognition receptor with anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb). Herein, we determined whether IFN-g modulated the levels of SLPI in TB patients. Plasma levels of SLPI and IFN-g were studied in healthy donors (HDs) and TB patients. Peripheral blood mononuclear cells from HDs and patients with TB or defective IFN-g receptor 1* were stimulated with Mtb antigen and SLPI, and IFN-gR expression levels were measured. Both SLPI and IFN-g were significantly enhanced in plasma from those with TB compared with HDs. A direct association between SLPI levels and the severity of TB was detected. In addition, Mtb antigen stimulation decreased the SLPI produced by peripheral blood mononuclear cells from HDs, but not from TB or IFN-gR patients. Neutralization of IFN-g reversed the inhibition of SLPI induced by Mtb antigen in HDs, but not in TB patients. Furthermore, recombinant IFN-g was unable to modify the expression of SLPI in TB patients. Finally, IFN-gR expression was lower in TB compared with HD peripheral blood mononuclear cells. These results show that Mtb-induced IFN-g down-modulated SLPI levels by signaling through the IFNgR in HDs. This inhibitory mechanism was not observed in TB, probably because of the low expression of IFN-gR detected in these individuals. (Am J Pathol 2014, 184: 1e6Fil: Tateosian, Nancy Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; ArgentinaFil: Pasquinelli, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Hernández Del Pino, Rodrigo Emanuel. Universidad de Buenos Aires; ArgentinaFil: Ambrosi, Nella Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; ArgentinaFil: Guerrieri, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; ArgentinaFil: Pedraza Sánchez, Sigifredo. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Santucci, Natalia Estefanía. Universidad Nacional de Rosario; ArgentinaFil: D'attilio, Luciano David. Universidad Nacional de Rosario; ArgentinaFil: Pellegrini, Joaquín Miguel. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Araujo Solis, María A.. Instituto Mexicano del Seguro Social; MéxicoFil: Musella, Rosa M.. Hospital "F. J. Muñiz"; ArgentinaFil: Palmero, Domingo J.. Hospital "F. J. Muñiz"; ArgentinaFil: Hernandez Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Garcia, Veronica Edith. Universidad de Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina; Argentin

Altered microRNA expression levels in mononuclear cells of patients with pulmonary and pleural tuberculosis and their relation with components of the immune response

Different lines of evidence demonstrate that microRNAs (miRNAs) play an important role in host–pathogen interactions. In this study we investigated the expression patterns of several miRNAs, most of them involved in regulating inflammatory responses, in patients with tuberculosis (TB). In order to understand the events occurring at the site of infection, we employed mononuclear cells obtained from both peripheral blood (PBMC) and pleural fluids (PFMC) of patients. Interestingly, we found that the miRNA signature of each compartment is different, with a strong down-regulation in PFMCs of miR-223, miR-144* and miR-421. In addition, we observed that miR-146a expression is also down-regulated in tuberculosis patients, both in PBMCs and PFMCs while miR-424 levels are elevated only in the peripheral compartments. We also showed that systemic expression of these miRNAs changes upon specific treatment and is associated with IL-6 levels, a cytokine playing a substantial role in TB immunopathology. Present results contribute to a better knowledge of the host responses in TB pathogenesis, pointing out the role of miRNAs in this disease.Fil: Spinelli, Silvana Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Díaz, Ariana. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: D'attilio, Luciano David. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marchesini, Marcela M.. Provincia de Santa Fe. Municipalidad de Rosario. Hospital "Mayor Gabriel Carrasco"; ArgentinaFil: Bogue, Cristina. Provincia de Santa Fe. Municipalidad de Rosario. Hospital "Mayor Gabriel Carrasco"; ArgentinaFil: Bay, Maria Luisa. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; ArgentinaFil: Bottasso, Oscar Adelmo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Effect of cortisol and/or DHEA on THP1-derived macrophages infected with Mycobacterium tuberculosis

Tuberculosis (TB) is a major health problem requiring an appropriate cell immune response to be controlled. Macrophages play a central role in the response against Mycobacterium tuberculosis (Mtb). Given our prior studies in which adrenal steroids were found to modify the cellular immune responses from TB patients, it was sensible to analyze the immunomodulatory capability of cortisol and DHEA on macrophages infected with Mtb. The human macrophage-like THP-1 cells were infected with the H37Rv strain of Mtb and treated with Cortisol and DHEA at different doses. We monitored phagocytosis, intracellular-bacterial growth, autophagosoma formation, as well as cytokine gene expression and production. Cultures exposed to cortisol showed a decreased production of IL-1β, TNF-α, with DHEA being unable to modify the pattern of cytokine production or to reverse the cortisol inhibitory effects. Interestingly the intra-macrophagic bacterial burden was found reduced by DHEA treatment. While this effect was not related to a different cytokine pattern, in terms their production or mRNA expression, DHEA treatment did promote autophagy in Mtb-infected macrophages, irrespective of Cortisol presence. In essence, the better control of Mtb load by DHEA-treated macrophages seems to be dependent on an autophagic mechanism. The present results are relevant for two reasons as autophagy is not only important for clearance of mycobacteria but also for the prevention of tissue damage.Fil: Bongiovanni, Bettina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Rosario. Instituto de Inmunología Clínica y Experimental de Rosario; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Mata Espinosa, Dulce. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: D'attilio, Luciano David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Rosario. Instituto de Inmunología Clínica y Experimental de Rosario; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Leon Contreras, Juan Carlos. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Marquez Velasco, Ricardo. Instituto Nacional de Cardiología Ignacio Chavez; MéxicoFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Rosario. Instituto de Inmunología Clínica y Experimental de Rosario; Argentina. Universidad Nacional de Rosario; ArgentinaFil: Hernandez Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán; MéxicoFil: Bay, Maria Luisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Rosario. Instituto de Inmunología Clínica y Experimental de Rosario; Argentina. Universidad Nacional de Rosario; Argentin

Levels of inflammatory cytokines, adrenal steroids, and mRNA for GRα, GRβ and 11βHSD1 in TB pleurisy

Our previous work on the immune-endocrine features of patients with pulmonary tuberculosis (TB) showed markedly decreased plasma levels of dehydroepiandrosterone (DHEA) together with augmented concentrations of Cortisol and pro- and anti-inflammatory cytokines. Studies in peripheral blood mononuclear cells (PBMC) indicated a lower mRNA α/β ratio of glucocorticoid receptors -GR- together with a higher 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) mRNA expression in cases with severe pulmonary TB. Since Pleural TB (PLTB) is a rather benign manifestation of TB, we now analyzed the systemic and local immune-endocrine profile as well as the GRα, GRβ, 11βHSD1 and 11βHSD2 transcripts in PBMC and pleural effusion mononuclear cells (PEMC) of patients with PLTB. PLTB patients had increased levels of IL-1β, IL-6 and IFNγ together with reduced Cortisol and DHEA concentrations in pleural fluids. Also, a significantly increased expression of 11βHSD1 and GRα was found in PEMC compared to PBMC. Findings point out to an appropriate immune response and a substantial inflammatory reaction, wherein the low Cortisol concentrations may be equally effective, because of the increased expression of GRα and 11βHSD1 transcripts which may optimize the immunomodulatory properties of Cortisol.Fil: D'attilio, Luciano David. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Díaz, Ariana. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Santucci, Natalia Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bongiovanni, Bettina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gardeñez, Walter. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Marchesini, Marcela. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital "Mayor Gabriel Carrasco"; ArgentinaFil: Bogué, Cristina. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Dídoli, Griselda. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; ArgentinaFil: Bottasso, Oscar Adelmo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bay, Maria Luisa. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentin

Immune response triggered by Trypanosoma cruzi infection strikes adipose tissue homeostasis altering lipid storage, enzyme profile and adipokine expression

Adipose tissue is a target of Trypanosoma cruzi infection being a parasite reservoir during the chronic phase in mice and humans. Previously, we reported that acute Trypanosoma cruzi infection in mice is linked to a severe adipose tissue loss, probably triggered by inflammation, as well as by the parasite itself. Here, we evaluated how infection affects adipose tissue homeostasis, considering adipocyte anabolic and catabolic pathways, the immune–endocrine pattern and the possible repercussion upon adipogenesis. During in vivo infection, both lipolytic and lipogenic pathways are profoundly affected, since the expression of lipolytic enzymes and lipogenic enzymes was intensely downregulated. A similar pattern was observed in isolated adipocytes from infected animals and in 3T3-L1 adipocytes infected in vitro with Trypanosoma cruzi. Moreover, 3T3-L1 adipocytes exposed to plasmas derived from infected animals also tend to downregulate lipolytic enzyme expression which was less evident regarding lipogenic enzymes. Moreover, in vivo-infected adipose tissue reveals a pro-inflammatory profile, with increased leucocyte infiltration accompanied by TNF and IL-6 overexpression, and adiponectin downregulation. Strikingly, the nuclear factor PPAR-γ is strongly decreased in adipocytes during in vivo infection. Attempts to favor PPAR-γ-mediated actions in the adipose tissue of infected animals using agonists failed, indicating that inflammation or parasite-derived factors are strongly involved in PPAR-γ inhibition. Here, we report that experimental acute Trypanosoma cruzi infection disrupts both adipocyte catabolic and anabolic metabolism secondary to PPAR-γ robust downregulation, tipping the balance towards to an adverse status compatible with the adipose tissue atrophy and the acquisition of an inflammatory phenotype.Fil: González, Florencia Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Villar, Silvina Raquel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Toneatto, Judith. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pacini, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Márquez, Julia. Universidad Nacional de Rosario; ArgentinaFil: D'attilio, Luciano David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Bottasso, Oscar Adelmo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Inmunología Clinica y Experimental de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología Clinica y Experimental de Rosario; ArgentinaFil: Piwien Pilipuk, Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Perez, Ana Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

TGF-β neutralization abrogates the inhibited DHEA production mediated by factors released from M. tuberculosis-stimulated PBMC

Supernatants (SN) from cultures of peripheral blood mononuclear cells (PBMC) of tuberculosis (TB) patients inhibit dehydroepiandrosterone (DHEA) secretion by the adrenal cell line NCI-H295R. To analyze whether TGF-β is involved in this effect, SN of PBMC from healthy controls or patients with severe TB infections, stimulated or not with Mycobacterium tuberculosis (Mtb SN), were added to adrenal cells under basal conditions or following stimulation with forskolin. Cortisol and DHEA concentrations were evaluated in supernatants of the adrenal cells cultured with or without the addition of anti-TGF-β. Treatment with Mtb SN from TB inhibited DHEA production, and this effect was reversed when SN were treated with anti-TGF-β. The increase in cortisol production induced by SN from TB patients was not affected by TGF-β neutralization. Mediators released during the anti-TB immune response differentially modulate steroid production by adrenal cells, and TGF-β is a cytokine implicated in the inhibition of DHEA production observed in TB.Fil: D'attilio, Luciano David. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Bozza, Verónica Vanina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Santucci, Natalia Estefanía. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Bongiovanni, Bettina. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Dídoli, Griselda. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; ArgentinaFil: Radcliffe, Stella. Hospital Provincial del Centenario; ArgentinaFil: Besedovsky, Hugo. Institut fur Physiologie und Pathophysiologie; AlemaniaFil: del Rey, Adriana. Institut fur Physiologie und Pathophysiologie; AlemaniaFil: Bottasso, Oscar Adelmo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Bay, Maria Luisa. Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Instituto de Inmunología; Argentin