RESUMO
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.
Assuntos
Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Tuberculose Pleural/genética , Tuberculose Pleural/metabolismo , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/metabolismo , Adolescente , Adulto , Idoso , Antituberculosos/uso terapêutico , Estudos de Casos e Controles , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Tuberculose Pleural/tratamento farmacológico , Tuberculose Pleural/imunologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , Adulto JovemRESUMO
We evaluated immune and endocrine status following antituberculosis treatment in HIV-negative patients with newly diagnosed tuberculosis (TB). Treatment led to a decrease in IL-6, IL-1ß, and C-reactive protein levels. Cortisol levels decreased throughout the anti-TB treatment, particularly after 4 months, but changes were less pronounced than those seen in proinflammatory mediators. Specific therapy resulted in increased dehydroepiandrosterone (DHEA) levels, which peaked after 4 months and started to decline after 6 months of treatment, reaching levels below those detected at inclusion. In contrast, in most patients, dehydroepiandrosterone sulfate (DHEAS) levels remained unchanged, although a trend toward increased concentrations was observed in a few cases 3 months after the treatment was finished. Specific therapy also resulted in more balanced cortisol/DHEA and cortisol/DHEAS ratios. Etiologic treatment involves favorable immune and endocrine changes, which may account for its beneficial effects.
Assuntos
Corticosteroides/sangue , Mediadores da Inflamação/sangue , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/imunologia , Adulto , Antituberculosos/uso terapêutico , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Desidroepiandrosterona/sangue , Sulfato de Desidroepiandrosterona/sangue , Feminino , Humanos , Hidrocortisona/sangue , Interleucina-1beta/sangue , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Tuberculose Pulmonar/tratamento farmacológico , Adulto JovemRESUMO
Earlier studies revealed that patients with tuberculosis (TB) have imbalanced immunoendocrine responses and that adrenal steroids [cortisol and dehydroepiandrosterone (DHEA)] can modify their specific cell-mediated immune response. Because most household contacts (HHCs) of contagious TB patients develop a subclinical and self-controlled process (latent TB), we studied some features of their immune and endocrine responses, particularly those related to the hypothalamic-pituitary-adrenal axis. Nineteen HHCs, 24 untreated TB patients (15 moderate, 9 advanced), and 18 healthy controls of similar age were studied. Patients had increased and reduced levels of cortisol and DHEA, respectively. DHEA levels were also reduced in HHCs. Stimulation of peripheral blood mononuclear cells (PBMC) with Mycobacterium tuberculosis sonicate resulted in increased in vitro lymphoproliferation in HHCs, while advanced patients showed the lowest response. Significantly higher amounts of interferon (IFN)-gamma were detected in supernatants from stimulated PBMC of HHCs when compared to controls and TB patients. Addition of cortisol to the cultures inhibited mycobacterial antigen-driven IFN-gamma production in all groups, although HHC supernatant contained significantly higher concentrations. In contrast, addition of DHEA to cultures of cells from HHCs resulted in increased IFN-gamma levels. These results suggest the existence of a particular immunoendocrine relation assuring a preserved IFN-gamma production in healthy housemates of TB patients.
Assuntos
Desidroepiandrosterona/imunologia , Características da Família , Hidrocortisona/imunologia , Interferon gama/biossíntese , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Adolescente , Adulto , Idoso , Antígenos de Bactérias/imunologia , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Desidroepiandrosterona/sangue , Desidroepiandrosterona/farmacologia , Feminino , Glucocorticoides/farmacologia , Humanos , Hidrocortisona/sangue , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Sonicação , Tuberculose/sangueRESUMO
BACKGROUND: The major protective immune response against intracellular bacteria, such as Mycobacterium tuberculosis, is a cell-mediated immunity involving neutrophils (PMNs) and peripheral mononuclear cells (MCs), contributing to the clearance of this microorganism and the resolution of the infection. This study was addressed to evaluate PMNs and MCs for their bactericidal function. METHODS: The sample comprised 14 tuberculosis (TB) inpatients (HIV-), and 10 healthy controls (HCo). Peripheral PMNs and MCs were separated by Ficoll-Hypaque and cultured in RPMI with or without heat-killed Mycobacterium tuberculosis (HK Mtb). Respiratory burst (RB), CD11b, IL-8 and TNFalpha receptor expression were assessed by flow cytometry in cells undergoing stimulation or not. Presence of IL-8 and TNFalpha in cell culture supernatants was determined by ELISA. RESULTS: TB patients had a lower RB response than HCo for both cell types (MCs, p <0.05, PMNs, p <0.01) regardless of HK Mtb stimulation. Compared to HCo, PMNs and MCs from TB patients presented a reduced CD11b expression, with the two subject groups showing a decrease in this marker expression following HK. Mtb was added to both cell cultures. Whereas fewer IL-8 and TNFalpha receptors were found when studying MCs and PMNs from TB patients, antigen stimulation significantly raised the expression for both cytokine receptors. Culture supernatants from MCs and PMNs of TB patients contained increased amounts of IL-8 and TNFalpha. CONCLUSIONS: The present findings may provide some explanation as to the different roles played by PMNs and MCs in TB immunopathology.
Assuntos
Citocinas/metabolismo , Leucócitos Mononucleares/imunologia , Neutrófilos/imunologia , Tuberculose/imunologia , Adulto , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Humanos , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Ativação de Neutrófilo , Neutrófilos/metabolismo , Explosão Respiratória , Tuberculose/sangue , Tuberculose/metabolismo , Tuberculose/microbiologiaRESUMO
Tuberculosis (TB) is the main cause of death by infection diseases worldwide. Considering that NO, TNF-alpha and TGF-beta participate a great deal in TB immunopathogenesis, we wished to analyse whether these mediators showed some relationship with the degree of pulmonary affectation. The sample comprised 29 TB (HIV-), inpatients with mild-moderate (n = 10) or advanced (n = 19) newly-diagnosed disease, together with 12 healthy controls HCo. Serum nitrite was assessed by reducing nitrate to nitrite, and further measured by the Griess reaction. Levels of TNF-alpha and TGF-beta were determined by ELISA (R&D Systems). Serum levels of TNF-alpha were significantly higher in the advanced TB cases if compared with HCo, (p < 0.05 ) and from values of Mild-Moderate TB patients (p < 0.05). Serum levels of TGF-beta from advanced TB patients have increased values if compared with Hco (p < 0.005) and Mild-Moderate patients (p < 0.05). These values were also significantly different from Mild-Moderate cases + HCo (p = 0.01) Advanced TB patients had significantly reduced nitrite levels compared with those of Mild-Moderate patients and HCo (p < 0.002). Taken as a whole NO-derived metabolites in TB patients (M-M and Advanced cases) remained lower than values in HCo (p = 0.005) A negative correlation was found when comparing the two cytokines with nitrites(r = -0.44 ).TGF-beta and TNF-alpha were positively correlated (r = 0.44, p < 0.01), 0.44, p < 0.01. In synthesis, the inverse correlation found between both cytokines concentrations and NO levels in TB patients may be viewed as a consequence of a more predominant TGF-beta effect.