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1.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809795

RESUMO

We previously showed that ubiquitous overexpression of the chromatin remodeling factor SWItch3-related gene (SRG3) promotes M2 macrophage differentiation, resulting in anti-inflammatory responses in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Since hepatic macrophages are responsible for sepsis-induced liver injury, we investigated herein the capacity of transgenic SRG3 overexpression (SRG3ß-actin mice) to modulate sepsis in mice exposed to lipopolysaccharide (LPS) plus d-galactosamine (d-GalN). Our results demonstrated that ubiquitous SRG3 overexpression significantly protects mice from LPS/d-GalN-induced lethality mediated by hepatic M1 macrophages. These protective effects of SRG3 overexpression correlated with the phenotypic conversion of hepatic macrophages from an M1 toward an M2 phenotype. Furthermore, SRG3ß-actin mice had decreased numbers and activation of natural killer (NK) cells but not natural killer T (NKT) cells in the liver during sepsis, indicating that SRG3 overexpression might contribute to cross-talk between NK cells and macrophages in the liver. Finally, we demonstrated that NKT cell-deficient CD1d KO/SRG3ß-actin mice are protected from LPS/d-GalN-induced sepsis, indicating that NKT cells are dispensable for SRG3-mediated sepsis suppression. Taken together, our findings provide strong evidence that SRG3 overexpression may serve as a therapeutic approach to control overwhelming inflammatory diseases such as sepsis.


Assuntos
Cromatina/metabolismo , Interferon gama/biossíntese , Interleucina-10/biossíntese , Fígado/patologia , Macrófagos/metabolismo , Células T Matadoras Naturais/metabolismo , Sepse/induzido quimicamente , Sepse/prevenção & controle , Fatores de Transcrição/metabolismo , Actinas/genética , Animais , Montagem e Desmontagem da Cromatina , Células Dendríticas/metabolismo , Galactosamina , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Substâncias Protetoras/metabolismo , Sepse/imunologia , Sepse/patologia , Índice de Gravidade de Doença
2.
Arterioscler Thromb Vasc Biol ; 41(3): e144-e159, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33406854

RESUMO

OBJECTIVE: ODC (ornithine decarboxylase)-dependent putrescine synthesis promotes the successive clearance of apoptotic cells (ACs) by macrophages, contributing to inflammation resolution. However, it remains unknown whether ODC is required for other arms of the resolution program. Approach and Results: RNA sequencing of ODC-deficient macrophages exposed to ACs showed increases in mRNAs associated with heightened inflammation and decreases in mRNAs related to resolution and repair compared with WT (wild type) macrophages. In zymosan peritonitis, myeloid ODC deletion led to delayed clearance of neutrophils and a decrease in the proresolving cytokine, IL (interleukin)-10. Nanoparticle-mediated silencing of macrophage ODC in a model of atherosclerosis regression lowered IL-10 expression, decreased efferocytosis, enhanced necrotic core area, and reduced fibrous cap thickness. Mechanistically, ODC deletion lowered basal expression of MerTK (MER tyrosine-protein kinase)-an AC receptor-via a histone methylation-dependent transcriptional mechanism. Owing to lower basal MerTK, subsequent exposure to ACs resulted in lower MerTK-Erk (extracellular signal-regulated kinase) 1/2-dependent IL-10 production. Putrescine treatment of ODC-deficient macrophages restored the expression of both MerTK and AC-induced IL-10. CONCLUSIONS: These findings demonstrate that ODC-dependent putrescine synthesis in macrophages maintains a basal level of MerTK expression needed to optimally resolve inflammation upon subsequent AC exposure. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Ornitina Descarboxilase/metabolismo , Putrescina/biossíntese , c-Mer Tirosina Quinase/metabolismo , Animais , Apoptose/fisiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Técnicas de Inativação de Genes , Histonas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Interleucina-10/biossíntese , Sistema de Sinalização das MAP Quinases , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Ornitina Descarboxilase/deficiência , Ornitina Descarboxilase/genética , Fagocitose/fisiologia , c-Mer Tirosina Quinase/genética
3.
APMIS ; 128(11): 593-602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870528

RESUMO

Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant-immunomodulators (like oil bodies) offer cost-effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed-derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli- derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund's (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1-biased cellular responses, manifested by high levels of IFN-γ and lower IgG1/IgG2a ratio and IL-4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN-γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT-PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL-10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola-derived antigen and oil bodies in addressing these concerns.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Células Th1/efeitos dos fármacos , Proteínas do Core Viral/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo de Brassica napus/administração & dosagem , Óleo de Brassica napus/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/virologia , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/imunologia , Vacinas contra Hepatite Viral/biossíntese
4.
Proc Natl Acad Sci U S A ; 117(35): 21519-21526, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32817517

RESUMO

The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.


Assuntos
Células Caliciformes/efeitos dos fármacos , Células Caliciformes/microbiologia , Indóis/farmacologia , Interleucina-10/metabolismo , Microbiota/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Envelhecimento/metabolismo , Animais , Bactérias/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Feminino , Células Caliciformes/citologia , Células Caliciformes/metabolismo , Interleucina-10/biossíntese , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Muco/metabolismo , Transdução de Sinais
5.
J Cancer Res Clin Oncol ; 146(8): 1971-1978, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32447484

RESUMO

PURPOSE: Interleukin-10 (IL-10) is an immunoregulatory cytokine and its cervical and serum concentrations have been associated with a poor prognosis of cervical cancer. The rs1800872 polymorphism (c.-592C>A) in the promotor region of the IL-10 gene affects the production and expression of IL-10 and thus is able to determine the immune response profile in the cervix. Therefore, the aim of this work is to state the association between IL-10 c.-592C>A polymorphism and cervical cancer. METHODS: Genomic DNA was extracted from patient's peripheral blood and tumor biopsy. Socio-demographic, sexual behavior and reproductive characteristics data were collected using a questionnaire. RESULTS: Co-dominant model in logistic binary regression adjusted for confounders, showed that patients presenting with C/A genotype had 2.15 times more chances for developing cervical cancer (OR 2.15; CI95% 1.02-4.56). The dominant model, C/A + A/A, was also independently associated with 2.71 times more chances for cervical cancer development when compared to control patients (OR 2.71; CI95% 1.05-4.47). CONCLUSION: Our study analyses show the association between cervical cancer and IL-10 c.-592C>A polymorphism, demonstrating that the allele A presence was independently associated with higher risks of cervical cancer development.


Assuntos
Interleucina-10/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Estudos de Casos e Controles , DNA/sangue , DNA/genética , Feminino , Genótipo , Humanos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/imunologia
6.
Sci Rep ; 10(1): 3897, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32127556

RESUMO

Co-expression of Yin Yang 1 (YY1) is required for the full function of the transcription factor, PLZF, which is essential for the development of natural killer T cell (NKT cell) effector functions. Discordant expression of YY1 and PLZF, therefore, might define NKT cell subsets with distinct effector functions. A subset of NKT cells was identified that expressed low levels of YY1. YY1lo NKT cells were found in all tissues, had a mature phenotype and, distinct from other NKT cells, expressed almost no ThPOK or Tbet. When activated, YY1lo NKT cells produced little IL-4 or IFN-γ. YY1lo NKT cells were found to constitutively transcribe IL-10 mRNA and, accordingly, produced IL-10 upon primary activation. Finally, we find that tumor infiltrating NKT cells are highly enriched for the YY1lo subset. Low YY1 expression, therefore, defines a previously unrecognized NKT cell subset that is committed to producing IL-10.


Assuntos
Interleucina-10/biossíntese , Células T Matadoras Naturais/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Linhagem Celular Tumoral , Cinética , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/citologia , Timo/imunologia
7.
Sci Adv ; 6(8): eaaz0374, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128419

RESUMO

Mucosal-associated invariant T (MAIT) cells in HIV-1-infected individuals are functionally impaired by poorly understood mechanisms. Single-cell transcriptional and surface protein analyses revealed that peripheral MAIT cells from HIV-1-infected subjects were highly activated with the up-regulation of interferon (IFN)-stimulated genes as compared to healthy individuals. Sustained IFN-α treatment suppressed MAIT cell responses to Escherichia coli by triggering high-level interleukin-10 (IL-10) production by monocytes, which subsequently inhibited the secretion of IL-12, a crucial costimulatory cytokine for MAIT cell activation. Blocking IFN-α or IL-10 receptors prevented MAIT cell dysfunction induced by HIV-1 exposure in vitro. Moreover, blocking the IL-10 receptor significantly improved anti-Mycobacterium tuberculosis responses of MAIT cells from HIV-1-infected patients. Our findings demonstrate the central role of the IFN-I/IL-10 axis in MAIT cell dysfunction during HIV-1 infection, which has implications for the development of anti-IFN-I/IL-10 strategies against bacterial coinfections in HIV-1-infected patients.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Interferon Tipo I/metabolismo , Interleucina-10/biossíntese , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Invariáveis Associadas à Mucosa/virologia , Terapia Antirretroviral de Alta Atividade , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/etiologia , Feminino , Infecções por HIV/complicações , HIV-1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária , Masculino , Transdução de Sinais
8.
Proc Natl Acad Sci U S A ; 117(13): 7305-7316, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32184325

RESUMO

Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4+CCR6+IL-7R+T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6+B helper T cells were phenotypically distinct from follicular helper T (TFH) cells and lacked BCL6 expression. In peripheral blood, a CCR6+T cell population with similar characteristics was identified, which lacked Th17- and TFH-associated gene signatures and differentiation-associated surface markers. CD4+CCR6+T cells expressing IL-10, but not IL-17, were also detectable in the spleens of cytokine reporter mice. They provided help for IgG production in vivo, and expanded systemically in pristane-induced lupus-like disease. In SLE patients, CD4+CCR6+IL-7R+T cells were associated with the presence of pathogenic anti-dsDNA (double-stranded DNA) antibodies, and provided spontaneous help for autoantibody production ex vivo. Strikingly, IL-10-producing CCR6+T cells were highly abundant in lymph nodes of SLE patients, and colocalized with B cells at the margins of follicles. In conclusion, we identified a previously uncharacterized population of extrafollicular B helper T cells, which produced IL-10 and could play a prominent pathogenic role in SLE.


Assuntos
Linfócitos B/imunologia , Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores CCR6/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Animais , Formação de Anticorpos , Criança , Citocinas/imunologia , Humanos , Interleucina-10/biossíntese , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Tonsila Palatina/citologia , Tonsila Palatina/imunologia , Receptores CCR6/biossíntese , Células Th17/imunologia
9.
Nat Commun ; 11(1): 1288, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152316

RESUMO

Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.


Assuntos
Receptores Imunológicos/metabolismo , Viroses/imunologia , Viroses/patologia , Doença Aguda , Animais , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-10/biossíntese , Fígado/patologia , Fígado/virologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Baço/imunologia
10.
J Orthop Surg Res ; 15(1): 54, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070384

RESUMO

BACKGROUND: To investigate the association between interleukin-6 (IL-6) (rs1800795, rs1800796, rs1800797, rs13306435, rs2069849) and interleukin-10 (IL-10) (rs1800871, rs1800896) gene polymorphisms, expression levels, and lumbar disc disease (LDD). METHODS: We conducted a literature research on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) until February 28, 2019. We included all case-control studies about the association between IL-6 and IL-10 gene polymorphisms and LDD. The odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of association. Statistical analysis was conducted by Review Manager (RevMan) 5.3 software. Furthermore, immunohistochemistry (IHC) and RT-PCR were performed to evaluate IL-6 and IL-10 expressions in the normal and degenerated disc. RESULTS: A total of 6 studies, involving 1456 cases and 1611 controls, were included in this meta-analysis. G alleles of rs1800795 and rs1800797 in the IL-6 gene were significantly associated with LDD (rs1800795: G vs. C, OR = 1.38, 95% CI = 1.16-1.64, P = 0.0002; rs1800797: G vs. A, OR = 1.35, 95% CI = 1.14-1.61, P = 0.0006). Begg's funnel plot and Egger's tests did not show any evidence of publication bias. IL-6 expression and IL-6 mRNA levels were significantly increased in the degenerated disc compared with those in the normal disc (IL-6 immunopositive cells, 73.68 ± 10.99% vs. 37.23 ± 6.42%, P < 0.001). CONCLUSIONS: IL-6 gene polymorphisms (rs1800795 and rs1800797) were significantly associated with susceptibility to LDD. A high expression level of IL-6 may be an important risk factor for LDD.


Assuntos
Interleucina-10/genética , Interleucina-6/genética , Degeneração do Disco Intervertebral/genética , Deslocamento do Disco Intervertebral/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Expressão Gênica , Predisposição Genética para Doença/genética , Humanos , Interleucina-10/biossíntese , Interleucina-6/biossíntese , Degeneração do Disco Intervertebral/metabolismo , Deslocamento do Disco Intervertebral/metabolismo , Vértebras Lombares
11.
Sci Rep ; 10(1): 1649, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015495

RESUMO

Cell-mediated immunity (CMI), IL-10, and the protective efficacy of modified-live porcine reproductive and respiratory syndrome virus (PRRSV) vaccines (MLV) against co-challenge with PRRSV-1 and PRRSV-2 (HP-PRRSV) were investigated. Seventy, PRRSV-free, 3-week old, pigs were allocated into 7 groups. Six groups were intramuscularly vaccinated with MLV, including Porcilis (PRRSV-1 MLV, MSD Animal Health, The Netherlands), Amervac (PRRSV-1 MLV, Laboratorios Hipra, Spain), Fostera (PRRSV-2 MLV, Zoetis, USA), Ingelvac PRRS MLV and Ingelvac PRRS ATP (PRRSV-2, Boehringer Ingelheim, USA), and Prime Pac PRRS (PRRSV-2 MLV, MSD Animal Health, The Netherlands). Unvaccinated pigs were left as control. Lymphocyte proliferative response, IL-10 and IFN-γ production were determined. At 35 days post-vaccination (DPV), all pigs were inoculated intranasally with 2 ml of each PRRSV-1 (105.4 TCID50/ml) and PRRSV-2 (105.2 TCID50/ml, HP-PRRSV). Following challenge, sera were quantitatively assayed for PRRSV RNA. Pigs were necropsied at 7 days post-challenge. Viremia, macro- and microscopic lung lesion together with PRRSV antigen presence were evaluated in lung tissues. The results demonstrated that, regardless of vaccine genotype, CMI induced by all MLVs was relatively slow. Increased production of IL-10 in all vaccinated groups was observed at 7 and 14 DPV. Pigs in Amervac, Ingelvac MLV and Ingelvac ATP groups had significantly higher levels of IL-10 compared to Porcilis, Fostera and Prime Pac groups at 7 and 14 DPV. Following challenge, regardless to vaccine genotype, vaccinated pigs had significantly lower lung lesion scores and PRRSV antigens than those in the control group. Both PRRSV-1 and PRRSV-2 RNA were significantly reduced. Prime Pac pigs had lowest PRRSV-1 and PRRSV-2 RNA in serum, and micro- and macroscopic lung lesion scores (p < 0.05) compared to other vaccinated groups. In conclusion, PRRSV MLVs, regardless of vaccine genotype, can reduce viremia and lung lesions following co-challenge with PRRSV-1 and PRRSV-2 (HP-PRRSV). The main difference between PRRSV MLV is the production of IL-10 following vaccination.


Assuntos
Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/prevenção & controle , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vacinas Virais/farmacologia , Animais , Imunidade Celular , Interferon gama/biossíntese , Interleucina-10/biossíntese , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/classificação , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , RNA Viral/sangue , RNA Viral/genética , Sus scrofa , Suínos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/farmacologia , Vacinas Virais/imunologia
12.
Mol Immunol ; 119: 92-100, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32006824

RESUMO

Regulatory B10 cells have been shown to exhibit impaired functions in autoimmune diseases. However, the underlying mechanism is still obscure. In the present study, we aimed to understand the regulatory characteristics of regulatory B10 cells and how these cells are involved in the development of rheumatoid arthritis (RA). Here, we chose CD19+CD24hiCD27+ as the phenotype of regulatory B10 cells. We found that the frequencies of CD19+CD24hiCD27+ regulatory B10 cells were decreased and that their IL-10-producing function was impaired in patients with RA compared with healthy controls (HCs). The impairment in CD19+CD24hiCD27+ B10 cells was partially attributed to the decreased expression of CD27 induced by the upregulated CD70 expression on CD19 + B cells and CD4 + T cells. The proportion of CD19+CD24hiCD27+ regulatory B10 cells could be restored by blocking the CD70-CD27 interaction with an anti-CD70 antibody. Furthermore, the CD70-CD27 interaction significantly elevated IL-10 expression and might compensate for the decreased number of CD19+CD24hiCD27+ B cells. Hence, the CD70-CD27 interaction might play a critical role in the numerical and functional impairments of regulatory B10 cells, thus contributing to RA pathogenesis. In conclusion, the change in CD19+CD24hiCD27+ regulatory B10 cells in RA was only a consequence, not the cause, of RA development, but the increased expression of CD70 might be the culprit.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos B Reguladores/imunologia , Ligante CD27/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Adulto , Antígenos CD19 , Linfócitos B Reguladores/metabolismo , Antígeno CD24 , Regulação para Baixo , Feminino , Humanos , Interleucina-10/biossíntese , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo
13.
Arch Virol ; 165(3): 583-592, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31927635

RESUMO

Interferon lambda was discovered in recent years to be an antiviral agent, and research on different aspects of this antiviral factor in viral infection and investigations of its effectiveness are also progressing. The immunological effects of interferon lambda on different cell populations is not precisely known, which may be due to its use of a heterodimeric receptor consisting of IL-10R2 and IFN-λR1, which are not broadly expressed in all types of cells. In the present study, signaling by interferon lambda and its effect on the expression of hepatitis C virus (HCV) proteins were measured, and the expression pattern of some antiviral proteins and IL-10 levels were investigated in peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 50 patients with chronic genotype 1a HCV infection and 10 healthy individuals as controls. The PBMCs were treated with various doses of interferon lambda at different times of cultivation. Real-time PCR was used for relative quantification of Mxa, PKR, OAS, ISG15 and HCV core mRNAs. Expression of the NS5A protein was measured by flow cytometry, and IL-10 production was assessed by ELISA. A significant increase in the expression of mRNA encoding antiviral proteins and a decrease in the expression of mRNAs encoding the HCV core protein were observed when cells were treated with interferon lambda in an intermittent manner. The expression of HCV NS5A protein and interleukin 10 levels were also lower than in the control group. It was shown that the maximum antiviral effect of interferon lambda in PBMCs is dependent on the dose and treatment time.


Assuntos
Hepatite C Crônica/imunologia , Interferons/farmacologia , Interleucinas/farmacologia , Leucócitos Mononucleares/imunologia , Proteínas do Core Viral/biossíntese , Proteínas não Estruturais Virais/biossíntese , Adulto , Antivirais/farmacologia , Linhagem Celular , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/imunologia , Interferon-alfa/farmacologia , Interferons/imunologia , Interleucina-10/biossíntese , Interleucinas/imunologia , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , RNA Mensageiro/biossíntese , RNA Viral/biossíntese , Proteínas do Core Viral/genética
14.
Nat Commun ; 11(1): 252, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937752

RESUMO

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Diferenciação Celular/imunologia , Cromatina/metabolismo , Colite/imunologia , Modelos Animais de Doenças , Epigênese Genética/imunologia , Fatores de Transcrição Forkhead/metabolismo , Trato Gastrointestinal/imunologia , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/metabolismo , Interleucina-10/biossíntese , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
15.
Clin Sci (Lond) ; 134(2): 123-138, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31922185

RESUMO

Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-ß and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.


Assuntos
Eosinófilos/imunologia , Inflamação/imunologia , Mucosa Nasal/imunologia , Mucosa Nasal/patologia , Sinusite/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Animais , Grupo com Ancestrais do Continente Asiático , Antígenos CD4/metabolismo , Doença Crônica , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Interleucina-10/biossíntese , Masculino , Camundongos Endogâmicos BALB C , Pólipos Nasais/sangue , Pólipos Nasais/complicações , Pólipos Nasais/genética , Pólipos Nasais/imunologia , Rinite/sangue , Rinite/complicações , Rinite/genética , Rinite/imunologia , Sinusite/sangue , Sinusite/complicações , Sinusite/genética , Células Th17/imunologia , Células Th2/imunologia , Fator de Crescimento Transformador beta/biossíntese
16.
Lasers Med Sci ; 35(6): 1341-1347, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31900691

RESUMO

Staphylococcus aureus is one of the main causative agent of infections acquired in both community and hospital environment. In this context, photodynamic therapy (PDT) consists in using a photosensitizer that, activated by light, evokes the formation of reactive oxygen species (ROS), which lead to the death of microorganisms due to oxidative damage; it is useful tool since this action, harmful to pathogens, does not significantly injure human cells. In view of this, this work proposes a more in-depth study on the use of resveratrol (RSV) as a possible photosensitizer. It was observed, in the intradermal infection model in animals' ear dermis, that photoactivated resveratrol promotes an increase in myeloperoxidase expression with reduced bacterial load in the draining lymph node. Besides that, the draining lymph node of the animals treated with photoactivated RSV controls inflammation through IL-10 production. These are pioneers data and this work being a pilot study; then, other works must be conducted with the objective of elucidate the photoactivated resveratrol mechanism of action.


Assuntos
Luz , Resveratrol/efeitos da radiação , Resveratrol/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Carga Bacteriana/efeitos dos fármacos , Caderinas/metabolismo , Derme/efeitos dos fármacos , Derme/enzimologia , Orelha/patologia , Humanos , Inflamação/patologia , Interleucina-10/biossíntese , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Projetos Piloto , Resveratrol/farmacologia , Staphylococcus aureus/efeitos dos fármacos
17.
Microb Pathog ; 139: 103891, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31783123

RESUMO

Previous study have shown that Talaromyces marneffei (T. marneffei) induced activation of autophagy. Therefore, we explore signaling pathway that regulates activation of autophagy by intracellular signaling mechanisms during T. marneffei infection. Further, we examine c-Jun N-terminal kinase 1 and 2 (JNK1/2) and p38 signaling pathways that regulate IL-1ß and IL-10 production and activation of autophagy during T. marneffei infection in human dendritic cells (DCs). We found that T. marneffei induced activation of JNK1/2 and p38 in human DCs. Furthermore, the inhibition of JNK1/2 and p38 increased activation of autophagy and decreased the replication of T. marneffei in T. marneffei-infected human DCs. Moreover, IL-1ß secretion in T. marneffei-infected human DCs was dependent on JNK1/2 and autophagy pathways, whereas IL-10 secretion was dependent on JNK1/2, p38 and autophagy pathways. These data suggest that JNK1/2 and p38 pathways play critical roles in activation of autophagy, the multiplication of T. marneffei and subsequent cytokine production during T. marneffei infection.


Assuntos
Autofagia , Células Dendríticas/metabolismo , Interleucina-10/biossíntese , Sistema de Sinalização das MAP Quinases , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Micoses/metabolismo , Micoses/microbiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Interleucina-1beta/biossíntese , Talaromyces
18.
Parasite Immunol ; 42(2): e12688, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31797390

RESUMO

Leishmania major causes mild-to-severe cutaneous lesions resulting in significant disfigurations, if untreated. The drugs are toxic, and drug-resistance parasites are emerging. Therefore, a prophylactic vaccination is an urgent need. As no vaccine is available, we compared the genes expressed by virulent and avirulent parasites. We identify L major adenylate kinase (AdeK) as a probable vaccine candidate after a series of experimentations. We cloned the gene in mammalian pcDNA6/HisA and pet28a+ vector for in vivo expression following immunization and in vitro protein expression for booster, respectively. We observed that immunization of susceptible BALB/c mice with AdeK resulted in significant protection against L major challenge infection. The protection was accompanied by increased IFN-γ producing lymphocytes and reduced IL-4, IL-17 and IL-10 secreting central and effector Th2, Th17 and Treg memory cells, respectively. These observations indicate L major AdeK as a potential vaccine candidate.


Assuntos
Adenilato Quinase/imunologia , Leishmania major/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose Cutânea/prevenção & controle , Proteínas de Protozoários/imunologia , Adenilato Quinase/administração & dosagem , Adenilato Quinase/genética , Animais , Suscetibilidade a Doenças , Feminino , Imunização Secundária , Memória Imunológica/imunologia , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-17/biossíntese , Interleucina-4/biossíntese , Leishmaniose Cutânea/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Células Th2/imunologia , Vacinação
19.
Parasite Immunol ; 42(2): e12687, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31770453

RESUMO

AIMS: This study aimed at evaluating the DNA vaccination efficacy of Leishmania major-derived MAPK10 against Leishmania donovani infection. METHODS AND RESULTS: MAPK10 is one of the 15 mitogen-activated protein kinases (MAPKs) of Leishmania major. Herein, we expressed the gene through a mammalian vector and tested whether priming with this gene would offer protection against L donovani infection. We report that LmjMAPK10 DNA vaccination using a mammalian expression vector significantly reduces the parasite burden. The protection is accompanied by host-protective T-cell functions, TH 1-type cytokines and elevated leishmanial antigen-specific IgG2a isotype response. T-cell response to the L donovani/challenge infection is associated with increase in IL-12 and IFN-γ, but reduced IL-10 and IL-4 production. CONCLUSIONS: LmjMAPK10 is cross-protective against L donovani infection.


Assuntos
Leishmania donovani/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose Visceral/prevenção & controle , Proteína Quinase 10 Ativada por Mitógeno/imunologia , Proteínas de Protozoários/imunologia , Vacinas de DNA/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Humanos , Imunoglobulina G/imunologia , Interferon gama/biossíntese , Interleucina-10/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Interleucina-4/biossíntese , Leishmania donovani/genética , Leishmaniose Visceral/imunologia , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase 10 Ativada por Mitógeno/genética , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/genética , Células Th1/imunologia
20.
Biochem Biophys Res Commun ; 522(2): 435-441, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31771884

RESUMO

Inflammatory bowel disease (IBD) is characterized by chronic, unpredictable relapsing and inflammatory disease of the gastrointestinal tract. Daily diet patterns have long been one of the most important hotspots for IBD therapeutic strategies. Sauchinone (SAU), a key bioactive lignin isolated from the roots of the herb Saururus chinensis, has been known to play an anti-inflammatory role in several diseases. However, its effect on IBD has not yet been investigated. In the current study, we established 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice and treated them with SAU. Flow cytometric analysis was performed to determine the phenotype of T cells in the lamina propria. qRT-PCR and ELISA were performed to measure cytokine transcript and protein levels, respectively. We found that SAU ameliorated TNBS-induced mouse colitis and inflammatory responses in mucosal tissues and peripheral blood CD4+ T cells from IBD patients. SAU significantly suppressed Th17 differentiation but facilitated IL-10 production, and SAU-treated Th17 cells exhibited inhibitory functions in vitro and in vivo. Mechanistically, we demonstrated that SAU induced Blimp-1 expression (encoded by Prdm1) in Th17 cells, and SAU failed to increase IL-10 production in Prdm1-knockout Th17 cells. Our data reveal an uncharacterized mechanism through which SAU regulates intestinal inflammation and Th17 differentiation.


Assuntos
Benzopiranos/uso terapêutico , Dioxóis/uso terapêutico , Inflamação/tratamento farmacológico , Interleucina-10/biossíntese , Intestinos/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Células Th17/imunologia , Animais , Benzopiranos/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Dioxóis/farmacologia , Humanos , Inflamação/patologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico
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