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1.
Biol Trace Elem Res ; 201(4): 1559-1566, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35486317

RESUMO

Sodium selenite modulates the activity of lymphocytes. It negatively regulates the suppressive activity of cells and increases the immune response. In this study, we evaluated whether the regulatory T cell differentiation was modulated by sodium selenite. The percentages of CD4+CD25+Foxp3+, CD4+CD25+, and CD4+CTLA-4+ cells in CD4+ T cells cultures stimulated with IL-2 and TGF-ß in the presence or absence of selenium, in the form of sodium selenite (2.0×10-6M), were evaluated by flow cytometry. The mRNA expression of TET2/3 enzymes and IL-10 was analyzed by RT-qPCR and the levels of IL-10 were measured by an ELISA. We observed a decrease in CD4+CD25+Foxp3+ and CD4+CTLA-4+ cells in presence of selenium. However, normal percentages were reached again after selenium removal. An increase in CD4+CTL4-4+ cells was detected in selenium-primed cell cultures in absence of IL-2 and TGF-ß. In addition, we observed a decrease in TET3 in presence of selenium. Finally, we observed an augment in IL-10 transcription and protein levels and relative expression of TET2 in cultures exposed to selenium. We suggest that selenium reversibly affects the regulatory T cell differentiation in vitro. Likewise, selenium may modulate Treg percentages promoting optimal immune responses and, at the same time, the expression of specific suppressor molecules.


Assuntos
Interleucina-10 , Selênio , Linfócitos T Reguladores/metabolismo , Selenito de Sódio/farmacologia , Selenito de Sódio/metabolismo , Antígeno CTLA-4/metabolismo , Selênio/farmacologia , Selênio/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Diferenciação Celular , Fatores de Transcrição Forkhead/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo
2.
Autoimmunity ; 55(7): 443-454, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35880661

RESUMO

The inflammasome AIM2 regulates multiple aspects of innate immune functions and serves as a critical mediator of inflammatory responses. AIM2 inflammasome activation leads to the production of pro-inflammatory cytokines, IL-1ß and IL-18 and participates triggering a pyroptosis response needed to counteract excessive cell proliferation. In addition, AIM2 expression and activation is wide regulated since alteration in its activity may derived in pathological consequences. Consequently, deregulated AIM2 activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of AIM2 inflammasome, as well as its contribution in rheumatoid arthritis and systemic lupus erythematous pathology. Finally, we highlight the participation of the AIM2-inflammasome at the level of joint in rheumatoid arthritis and at kidney in systemic lupus erythematous. The development of therapeutic strategies based on modulation of AIM2-inflammasome activity should have a tissue-specific focus.


Assuntos
Artrite Reumatoide , Proteínas de Ligação a DNA , Inflamassomos , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-18
3.
Exp Mol Pathol ; 123: 104689, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34592200

RESUMO

The aim of this study was to analyze the expression of mBD4, mBD3 and CRAMP in joint of mice with type II collagen-induced arthritis/CIA and to explore its possible association with IL-10, IL-4, IFN-γ, IL-17, MMP3, RANK/RANKL/OPG and histological parameters. METHODS: CIA was induced in 44 DBA/1 J mice. The joints from mice were classified into the onset, peak and remission phase of CIA. Histological sections were stained with hematoxylin-eosin and safranin O. The expression of CRAMP, mBD-3, mBD-4, and MMP-3 was evaluated using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The expression of IL-10, IL-4, IFN-γ, IL-17, RANK/RANKL/OPG was analyzed by RT-PCR. RESULTS: We observed that inflammation and immunostained cells for CRAMP increased in the peak and remission phases compared to the control group. In addition, increments in relative expressions of CRAMP were detected for the remission phase and in IL-4 and IL-17 in the peak phase compared to the control and onset phase. In addition, an increase in IL-10 in a peak phase compared to the control, as well as the relative expression of IFN-γ in remission phase was higher than in the onset phase. This was accompanied by an increase in cartilage damage in the peak phase compared to the control. Cells immunostained to MMP3 increased in the peak phase compared to the onset and control group, and relative expression of MMP3 was detected in the peak phase compared to the onset, remission, and control group. We observed that the relative expression of RANK and RANKL in the peak phase was higher than in control and onset phase. Finally, the relative expression of OPG in the peak phase compared to the onset, remission, and control group was detected. Regarding CRAMP behavior in the different phases studied, it was positively correlated with IL-4 and RANK, and showed a negative correlation with IFN-γ, IL-17, IL-10, RANKL, OPG and RANKL/OPG ratio in the control group. Also was positively correlated with IFN-γ, IL-17, IL-4, IL-10, as well as with RANK, RANKL, and OPG in the onset and peak phases of the CIA. In the peak phase, CRAMP showed a positive association with MMP3, and we observed a direct correlation between CRAMP and IFN-γ and RANKL/OPG ratio in remission phase. mBD3 correlates positively with IFN-γ, IL-17, IL-10, RANKL, OPG and RANKL/OPG ratio, and showed a negative correlation with CRAMP, MMP3, and RANK in the control group. Also, it was directly associated with IFN-γ, IL-17, IL-4, IL-10 and RANKL in the onset phase while it was inversely associated with CRAMP, MMP-3, RANK, RANKL, and OPG in the peak phase. Finally, mBD3 was inversely correlated with MMP3 in the remission phase and was directly associated with CRAMP, IFN-γ and RANKL/OPG ratio in this phase. mBD4 was directly associated with CRAMP, IFN-γ, IL-17, IL-4, IL-10, RANKL / OPG in the onset phase, and with CRAMP, IFN-γ, IL-17, IL-4, IL-10, MMP3, RANK, RANKL and OPG in the peak phase. Finally, mBD4 was positively associated with mBD3, IFN-γ, IL-17, IL-10, RANK, RANKL OPG and RANKL/OPG in the CIA remission phase. CONCLUSIONS: Our results demonstrate that CRAMP plays an important role in CIA progress and suggest that its abundance is associated with local pro- and anti-inflammatory status. This makes us propose CRAMP as a possible contributor of bone reconstruction in the last stage of CIA.


Assuntos
Artrite/genética , Remodelação Óssea/genética , Catelicidinas/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , beta-Defensinas/genética , Animais , Artrite/induzido quimicamente , Artrite/patologia , Colágeno Tipo II/toxicidade , Regulação da Expressão Gênica/genética , Humanos , Inflamação/genética , Inflamação/patologia , Camundongos
4.
Diabetes Res Clin Pract ; 173: 108692, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33571599

RESUMO

AIM: To determine the percentages of (CD19 + CD24 + CD38+, CD19 + CD24 + CD27+, CD19 + IL-10+)-Breg cells, IL-17 single and IL-17+/IFN-γ double producers T cells and IFN-γ+ T cells, in normal-glycemic individuals, prediabetes and T2DM patients, and to analyze the association of Breg cells with metabolic parameters of T2DM. METHODS: percentages of Breg cells, IL-17+ and IL-17 + IFN-γ+ T cells, IFN-γ+ T cells and IL-10 were determined by flow cytometry. IL-6 levels were evaluated by ELISA assay. RESULTS: increased IL-6 levels, IL-17+ and IL-17 + IFN-γ+ T cells and a diminution of IL-10 levels and CD19 + IL-10+ cells in T2DM patients were observed. We found that CD19 + CD24 + CD27+ cells and CD19 + CD24 + CD38+ cells were increased in T2DM patients. The percentages of CD19 + CD24 + CD38+ cells were associated with HOMA-B, TyG index, HDL and cholesterol values. In normal-glycemic individuals, CD19 + CD24 + CD27+ cells were inversely associated to triglycerides and TyG index. In prediabetes patients, CD19 + CD24 + CD38+ cells were inversely related with cholesterol and LDL. Finally, CD19 + CD24 + CD38+ cells were inversely related with HDL values in T2DM patients. CONCLUSION: Our results suggest that increased percentages of IL-17 single and IL-17/IFN-γ double producers T cells in T2DM patients may be a consequence of the initial CD19 + IL-10+ cells reduction. Furthermore, dyslipidemia could play an important role in percentages and activity of B regulatory cells.


Assuntos
Linfócitos B Reguladores/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Estado Pré-Diabético/metabolismo , Adulto , Feminino , Humanos , Masculino
5.
Toxicol Lett ; 280: 92-98, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28823542

RESUMO

UROtsa cells have been accepted as a model to study carcinogenicity mechanisms of arsenic-associated human bladder cancer. In vitro continuous exposure to monomethylarsonous acid (MMAIII), leads UROtsa cells to commit to malignant transformation. In this process, NF-κß-associated inflammatory response seems to play an important role since this transcription factor activates some minutes after cells are exposed in vitro to MMAIII and keeps activated during the cellular malignant transformation. It is known that a slight decrease in the protein phosphatase and tensin homologue (PTEN) gene expression is enough for some cells to become malignantly transformed. Interestingly, this tumor suppressor has been proven to be negatively regulated by NF-κß through binding to its gene promoter. Based on these observations we propose that NF-κß may be involved in arsenic associated carcinogenesis through the negative regulation of PTEN gene expression. Changes in PTEN expression and the binding of p50 NF-κß subunit to PTEN promoter were evaluated in UROtsa cells exposed for 4, 12, 20, or 24 wk to 50nM MMAIII. Results showed that MMAIII induced a significant decrease in PTEN expression around 20 wk exposure to MMAIII,which correlated with increased binding of p50 subunit to the PTEN promoter. Consistent with these results, ChIP assays also showed a significant decrease in H3 acetylation (H3ac) but an increase in the repression marks H3k9me3 and H327me3 in PTEN promoter when compared with not treated cells. These results suggest that the activation of NF-κß by MMAIII may participate in UROtsa cells malignant transformation through the negative regulation of PTEN expression involving p50 homodimers-mediated chromatin remodeling around the PTEN promoter.


Assuntos
Histonas/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Compostos Organometálicos/toxicidade , PTEN Fosfo-Hidrolase/metabolismo , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica/fisiologia , Histonas/genética , Humanos , Metilação , Subunidade p50 de NF-kappa B/genética , PTEN Fosfo-Hidrolase/genética , Regiões Promotoras Genéticas
7.
Neurochem Res ; 41(10): 2559-2572, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27321306

RESUMO

Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells. Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMAIII), which accumulates in glial cells without compromising cell viability. MMAIII LD50 in astrocytes was 10.52 µM, however, exposure to sub-toxic MMAIII concentrations (50-1000 nM) significantly increased IL-1ß, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and ß-secretase (BACE-1) increased gene expression, mainly for those MMAIII concentrations that also induced TNF-α over-expression. Other effects of MMAIII on cortical astrocytes included increased proliferative and metabolic activity. All tested MMAIII concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMAIII induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Astrócitos/efeitos dos fármacos , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Homeostase/efeitos dos fármacos , Ratos Wistar
8.
Cell Immunol ; 289(1-2): 167-73, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24841855

RESUMO

We have hypothesized that individuals infected with Mycobacteriumtuberculosis that exhibit different patterns of immune reactivity in serial interferon (IFN)-γ release assays (IGRA's) correspond to different status within the immune spectrum of latent tuberculosis (TB). Accordingly, we analyzed the possible association between the consistent results (negative or positive) in an IGRA test and relevant immune parameters, mainly the levels of Th1 and Th17 lymphocytes and T regulatory (Treg) cells in the peripheral blood of TB case contacts. We found that individuals with a persistently positive IGRA showed increased levels of Th1 and Th17 lymphocytes upon in vitro stimulation with MTB antigens. In addition, a significant increase in the proportion of CD4+CTLA-4+ and CD4+Foxp3+ cells was detected in assays with blood samples from these individuals. Our data support that different immune phenotypes can be identified into the spectrum of latent TB, by combining different parameters of immune reactivity against MTB.


Assuntos
Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Mycobacterium tuberculosis/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Antígenos CD4/sangue , Antígeno CTLA-4/sangue , Feminino , Fatores de Transcrição Forkhead/sangue , Humanos , Interferon gama/imunologia , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Masculino
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