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1.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(9): 1077-1083, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31594149

RESUMO

Objective: To investigate the influence of IFN-γ and IL-12 levels in prenatal peripheral blood of HBsAg-positive parturients on intrauterine transmission of hepatitis B virus (HBV). Methods: A case-control study was conducted in 282 HBsAg positive parturients and 43 health parturients (control group) in Northwest Women and Children Hospital of Shaanxi Province. Enzyme-linked immunosorbent assay (ELISA) was used to detect five serological makers of hepatitis B in peripheral blood of parturients. HBV DNA was detected by real-time fluorescence quantitative PCR. Detection of cytokines IFN-γ and IL-12 levels were conducted with liquid chip-based flow cytometry method. The serum levels of five serological markers of hepatitis B and HBV DNA in 285 newborns were detected within 24 hours after birth. Results: The incidence of intrauterine dominant infection (DBI), occult infection (OBI) and intrauterine transmission of HBV in HBsAg positive parturients were 7.37% (21/285), 40.70% (116/285) and 48.07% (137/285), respectively. The level of IFN-γ in peripheral blood of HBsAg-negative parturients was significantly lower than those of HBsAg-positive parturients (t=-2.55, P=0.011), NBIT group (t=-2.54, P=0.012) and OBI group (t=-2.33, P=0.021). In HBV DNA load of 10(3)-10(6) copies/ml group, the levels of IFN-γ in the DBI group were significantly lower than those in OBI group and NBIT group (P<0.01). The level of IFN-γ in maternal peripheral blood decreased significantly with the increased severity of intrauterine transmission of HBV (χ(2)=6.40, P=0.041). In the antiviral treatment group, the level of IL-12 in maternal peripheral blood decreased significantly with the increased severity of intrauterine transmission of HBV (χ(2)=8.90, P=0.012). Multivariate analysis showed that there was a significant linear relationship between maternal IFN-γ level and maternal age, placenta previa and hepatitis B vaccine injection (P<0.05). The linear relationship between the level of maternal IL-12 and the mode of rupture and hepatitis B vaccine injection had statistical significance (P<0.05). Conclusions: HBV can stimulate the expression of IFN-γ and inhibit the secretion of IL-12 in pregnant and lying-in women, but the expression of IFN-γ in HBsAg-positive parturients showed intra-group differentiation, and the maternal level of IFN-γ will decrease in HBeAg-positive and high-HBV DNA loadstatus. Increasing the levels of IFN-γ and IL-12 in HBsAg-positive parturients is beneficial to block intrauterine transmission of HBV, especially DBI.


Assuntos
Hepatite B , Interleucina-12/metabolismo , Complicações Infecciosas na Gravidez , Estudos de Casos e Controles , Criança , DNA Viral , Feminino , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Interferon gama/metabolismo , Gravidez
2.
Artigo em Inglês | MEDLINE | ID: mdl-31327402

RESUMO

The interleukin (IL)-12 family of cytokines, including IL12 and IL 23, play an important role in driving aberrant Th1 and Th17 immune responses in patients with Crohn's disease (CD). Targeting this pathway has opened new avenues for therapeutic intervention. The approval of ustekinumab, a monoclonal antibody blocking the common p40 subunit of IL12 and IL23, marked an important evolution in medical management for CD: this novel class of biologic therapy demonstrated efficacy in both patients naïve to biologics as well as in patients experiencing inadequate response or loss of response to TNF antagonists. However, as our understanding of the IL12/23 pathway has evolved, specific targeting of IL23 through its unique p19 subunit has become a focus for novel therapeutic development. IL23p19 antagonists have been shown in head-to-head trials to have superior efficacy to ustekinumab for other immune-mediated conditions such as psoriasis. In CD, phase II trials of monoclonal antibodies targeting IL23, including risankizumab and brazikumab, have shown promising results, with multiple agents now entering phase II or phase III studies. In this review, we summarize the current evidence for both anti-IL12/23p40 and anti-IL23p19 monoclonal antibodies in CD.


Assuntos
Doença de Crohn/terapia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Doença de Crohn/patologia , Humanos
3.
Microbiol Immunol ; 63(9): 367-378, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273816

RESUMO

Heat-killed Lactobacillus plantarum L-137 (HK L-137), an immunobiotic lactic acid bacterium, has been reported to enhance IFN-γ production through induction of IL-12. In this study, we investigated the effects of HK L-137 on skin moisturizing and production of hyaluronic acid (HA), an extracellular matrix associated with the retention of skin moisture. Oral administration of HK L-137 suppressed the loss of water content in the stratum corneum in hairless mice. Treatment of primary epidermal cells with HK L-137 increased HA production. Supernatant from immune cells stimulated by HK L-137, which contained proinflammatory cytokines such as IL-12, TNF-α, and IFN-γ, upregulated HA production and hyaluronan synthase 2 (HAS2) messenger RNA expression by BALB/3T3 fibroblasts via activation of transcription factor nuclear factor κB (NFκB). Although treatment of the supernatant with anti-TNF-α antibody (Ab) alone did not inhibit the HA production, combination of anti-TNF-α Ab with anti-IFN-γ Ab significantly inhibited the HA production. Thus, HK L-137-induced IFN-γ plays a critical role in upregulated HA production in collaboration with TNF-α. HK L-137 may be useful for improvement of skin functions such as moisture retention by inducing HA production.


Assuntos
Citocinas/metabolismo , Células Epidérmicas/metabolismo , Fibroblastos/metabolismo , Ácido Hialurônico/metabolismo , Lactobacillus plantarum/fisiologia , Animais , Células 3T3 BALB , Fator de Crescimento Epidérmico/metabolismo , Feminino , Hialuronan Sintases , Interferon gama/metabolismo , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/metabolismo , Pele , Baço , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Carbohydr Polym ; 218: 37-45, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31221341

RESUMO

Polysaccharides were extracted from Schizophyllum commune (a common mushroom) and their structural and immune-enhancing properties were investigated. Crude and fractions (F1 and F2) were composed of sugars (50.3-82.8%), proteins (1.46-20.1%), and sulfates (1.33-7.01%). Monosaccharide compositions of Cr and F1 were mainly composed of glucose (75.5% and 88.2%) with small amounts of mannose, galactose and xylose whereas the F2 was mainly composed of manose (55.2%) with minor amounts of galactose, glucose, and xylose. Their immune-enhancing activities were tested using RAW264.7 cells. Proliferation activity of RAW264.7 cells was over 100% after treatment with these polysaccharides. In addition, RAW264.7 cells produced large amounts of nitric oxide and various cytokines by up-regulating mRNA expression levels and the activation of nuclear factor-kappa (NF-κB) and mitogen-activated protein kinase (MAPK) after treatment with these polysaccharides. In addition, RAW264.7 cells were activated mainly through CR-3 and TLR-4 receptors. The backbone of F2 with excellent immune-enhancing activity was mainly linked by (1→3)-linked-mannopyranosyl and (1→2,3)-linked-mannopyranosyl residues.


Assuntos
Fatores Imunológicos/farmacologia , Mananas/farmacologia , Schizophyllum/química , Animais , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mananas/química , Mananas/isolamento & purificação , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Peso Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Receptores de Complemento/metabolismo , Receptor 4 Toll-Like/metabolismo
5.
World J Microbiol Biotechnol ; 35(6): 91, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31161259

RESUMO

The limited efficacy of available influenza vaccines against rapidly emerging new viral strains stresses the need for the development of new antigen-independent prophylactic treatment for enhancing immunity against influenza infection. Recent studies suggest that probiotics possess immunomodulatory properties and can reduce the severity of respiratory infections. Here, we investigated the potential of prophylactic Bifidobacterium bifidum in improving anti-influenza immune responses in an experimental lethal mouse-adapted influenza A (H1N1) infection in a BALB/c mouse model. One week after viral challenge, splenocyte proliferation assay (MTT), IFN-gamma, IL-12, and IL-4 in spleen and IL-6 in the lung homogenates were conducted using ELISA assays. Sera samples were collected to measure IgG1 and IgG2a levels. Furthermore, the mice challenged with lethal influenza virus were assessed for survival rate. The findings demonstrated a strong induction of both humoral and cellular immunities, as well as decreased level of IL-6 production in the lung and an increase in survival rate in the mice receiving Bifidobacterium than those of the control group were observed. Taken together, the results indicate a robust potential for Bifidobacterium to modulate humoral and cellular immune responses and induce balanced Th1/Th2 immune responses against influenza infection.


Assuntos
Bifidobacterium bifidum/fisiologia , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Probióticos/farmacologia , Animais , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Cães , Feminino , Humanos , Imunidade Celular , Imunidade Humoral , Imunização , Imunoglobulina G/sangue , Imunomodulação , Vírus da Influenza A Subtipo H1N1/patogenicidade , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Pulmão/imunologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos BALB C , Baço/imunologia , Taxa de Sobrevida , Células Th1/imunologia , Células Th2/imunologia
6.
Am J Chin Med ; 47(4): 823-839, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091972

RESUMO

Ginseng root has been used in traditional oriental medicine for the enhancement of immune system function. The immunostimulatory effects of ginseng berry polysaccharides, however, remain unclear. Effects of polysaccharides from ginseng berry on the activation of natural killer (NK) cells and inhibition of tumors are reported. A crude polysaccharide was isolated from ginseng berry as a ginseng berry polysaccharide portion (GBPP) and was further fractionated using gel filtration chromatography to obtain the three polysaccharide fractions GBPP-I, -II and -III. GBPP-I consisted of mainly galactose (46.9%) and arabinose (27.5%). GBPP-I showed a high dose-dependent anticomplementary activity. Stimulation of murine peritoneal macrophages by GBPP-I showed the greatest enhancement of interleukin (IL)-6 and IL-12 and tumor necrosis factor (TNF)- α production. In addition, an ex vivo assay of natural killer (NK) cell activity showed that oral ( p.o.) administration of GBPP-I significantly increased NK cell cytotoxicity in YAC-1 tumor cells and production of granzyme B. Prophylactic intravenous ( i.v.) and p.o. administration of GBPP-I significantly and dose-dependently inhibited lung metastatic activity in B16BL6 melanoma cells. Depletion of NK cells after injection of rabbit anti-asialo GM1 partially abolished the inhibitory effect of GBPP-I on lung metastasis, indicating that NK cells play an important role in anticancer effects. GBPP-I exerts a strong immune-enhancing activity and can prevent cancer metastasis through activation of NK cells and other immune-related cells.


Assuntos
Adjuvantes Imunológicos , Proteínas Inativadoras do Complemento , Frutas/química , Macrófagos Peritoneais/imunologia , Panax/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Células Matadoras Naturais/imunologia , Macrófagos Peritoneais/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Polissacarídeos/administração & dosagem , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismo
7.
Exp Parasitol ; 203: 1-7, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31128104

RESUMO

Fucose-mannose ligand (FML) is a soluble antigen purified from Leishmania donovani complex and used for diagnosis, prognosis, and vaccine development against visceral leishmaniasis (VL). We aimed to explore the effects of FML on the production of cytokines, chemokines and nitric oxide (NO) by macrophages in vitro. Peritoneal macrophages from BALB/c mice were treated with various concentrations of FML purified from Leishmania infantum in the absence or presence of LPS Peritoneal macrophages. After 48hr, cell culture supernatants were recovered and the levels of TNF-α, IL-10, IL-12p70 and IP-10 measured by Sandwich ELISA and NO concentration by Griess reaction. We found that FML significantly increase NO, IL-12p70 and IP-10 production in both LPS-treated and untreated macrophages and increase IL-10 levels only in LPS-treated macrophages. However, FML could not alert TNF-α levels in both LPS-treated and untreated macrophages. Further analysis revealed that FML can also increase IL-12p70/IL-10 ratio in LPS-treated macrophages. We concluded that FML can polarize macrophages to an appropriate phenotype similar to M1 phenotype against Leishmania donovani complex, although IL10 and TNF results are controversial.


Assuntos
Citocinas/metabolismo , Lectinas/farmacologia , Leishmania infantum/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Óxido Nítrico/metabolismo , Animais , Quimiocina CXCL10/metabolismo , Feminino , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Leishmania infantum/imunologia , Ativação de Macrófagos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/metabolismo
8.
Cell Physiol Biochem ; 52(6): 1325-1338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050281

RESUMO

BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory cardiovascular disease. Macrophages are major components of atherosclerotic plaques and play a key role in the development of atherosclerosis by secreting a variety of pro-inflammatory factors. Our previous studies have confirmed that upconversion nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) mediated photodynamic therapy (PDT) can promote cholesterol efflux and induce apoptosis in THP-1 macrophages. In this study, we investigated whether reactive oxygen species (ROS) generated by UCNPs-Ce6-mediated PDT can induce autophagy to inhibit the expression of pro-inflammatory factor in M1 peritoneal macrophages. METHODS: Peritoneal macrophages were collected from C57/BL6 mice injected with 3% thioglycollate broth medium and induced by lipopolysaccharides and interferon-γ. Intracellular ROS production was assessed by 2'-7'-dichloroflorescein diacetate and flow cytometry. Autophagy was assayed by western blot, transmission electron microscopy and immunofluorescence. Pro-inflammatory cytokines were detected by enzyme-linked immunosorbent assay and western blot. RESULTS: Model M1 peritoneal macrophages were established after 24 h induction. Protein expression levels of LC3 II and Beclin1, and degradation of p62 increased and peaked at 2 h in the PDT group. Meanwhile, levels of inflammatory cytokines iNOS, IL-12, and TNF-α markedly decreased after PDT. The increase in autophagy levels and decrease in pro-inflammatory cytokines were significantly inhibited by 3-methyladenine. Furthermore, ROS generated by UCNPs- Ce6 mediated PDT activated autophagy. The expression of autophagy related-protein and inflammatory cytokines iNOS, IL-12, and TNF-α were inhibited by the ROS inhibitor N-acetyl cysteine. CONCLUSION: ROS generated by UCNPs-Ce6-mediated PDT activated autophagy and inhibited the expression of pro-inflammatory factors of M1 peritoneal macrophage via the PI3K/AKT/mTOR signaling pathway.


Assuntos
Autofagia/efeitos dos fármacos , Nanopartículas Metálicas/química , Porfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Proteína Beclina-1/metabolismo , Interleucina-12/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fotoquimioterapia , Porfirinas/química , Porfirinas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
EBioMedicine ; 43: 380-391, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30992245

RESUMO

BACKGROUND: Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS: NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. FINDINGS: During systemic inflammation, the expression of the IL-12 receptor ß2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor ß receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor ß2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION: GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.


Assuntos
Antígeno CD56/metabolismo , Infecção Hospitalar/etiologia , Infecção Hospitalar/metabolismo , Fator 15 de Diferenciação de Crescimento/sangue , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Adulto , Biomarcadores , Comorbidade , Infecção Hospitalar/sangue , Infecção Hospitalar/diagnóstico , Feminino , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-12/metabolismo , Masculino , Pessoa de Meia-Idade , Fosforilação , Receptores de Interleucina-12/metabolismo , Fator de Transcrição STAT4/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/metabolismo
10.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925680

RESUMO

During the past two decades, recombinant human interleukin-12 (rhIL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models and clinical studies. Purity is a critical quality attribute (CQA) in the quality control system of rhIL-12. In our study, rhIL-12 bulks from manufacturer B showed a different pattern in non-reduced SDS-PAGE compared with size-exclusion chromatography (SEC)-HPLC. A small fragment was only detected in non-reduced SDS-PAGE but not in SEC-HPLC. The results of UPLC/MS and N-terminal sequencing confirmed that the small fragment was a 261⁻306 amino acid sequence of a p40 subunit of IL-12. The cleavage occurs between Lys260 and Arg261, a basic rich region. With the presence of 0.2% SDS, the small fragment appeared in both native PAGE and in SEC-HPLC, suggesting that it is bound to the remaining part of the IL-12 non-covalently, and is dissociated in a denatured environment. The results of a bioassay showed that the fractured rhIL-12 proteins had deficient biological activity. These findings provide an important reference for the quality control of the production process and the final products of rhIL-12.


Assuntos
Eletroforese em Gel de Poliacrilamida/métodos , Interleucina-12/metabolismo , Proteínas Recombinantes/metabolismo , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Humanos , Interleucina-12/isolamento & purificação , Modelos Moleculares , Peso Molecular , Desnaturação Proteica , Proteínas Recombinantes/isolamento & purificação , Análise de Sequência de Proteína
11.
EBioMedicine ; 41: 333-344, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30827928

RESUMO

BACKGROUND: Innate lymphoid cells (ILCs) are a newly discovered family of immune cells that have similar cytokine-secreting profiles as T helper cell subsets. Although ILCs are critical for host defense against infections and tissue homeostasis, their roles in tumor development are not well established. METHODS: We studied the function of ILC3 cells in the liver for the development of hepatocellular carcinoma (HCC) in murine HCC models using flow cytometry, adoptive transfer, and in vitro functional assays. FINDINGS: We found that ILC3 lacking the natural cytotoxicity-triggering receptor (NCR-ILC3) promoted the development of HCC in response to interleukin 23 (IL-23). IL-23 serum level is elevated in HCC patients and its high expression is associated with poor clinical outcomes. We found that IL-23 could promote tumor development in murine HCC tumor models. IL-23 promoted the expansion of NCR-ILC3 and its differentiation from group 1 ILCs (ILC1s). Furthermore, NCR-ILC3 initiated IL-17 production upon IL-23 stimulation and directly inhibited CD8+ T cell immunity by promoting lymphocyte apoptosis and limiting their proliferation. INTERPRETATION: Together, our findings suggest that NCR-ILC3 initiates the IL-17-rich immunosuppressive tumor microenvironment and promotes the development of HCC, thus may serve as a promising target for future cancer immunotherapy. FUND: This work was supported by grants from National Natural Science Foundation of China (81471586, 81571556), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the collaborative Innovation Center of Hematology, start-up grant from National University of Singapore, the Cancer Prevention and Research Institute of Texas CPRIT (RR180017), and the National Cancer Institute's Cancer Center Support (Core) Grant CA016672 (to The University of Texas MD Anderson Cancer Center).


Assuntos
Carcinoma Hepatocelular/patologia , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Neoplasias Hepáticas/patologia , Animais , Apoptose , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Técnicas de Cocultura , Modelos Animais de Doenças , Imunidade Inata , Interleucina-12/metabolismo , Interleucina-17/análise , Interleucina-23/análise , Interleucina-23/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidades Proteicas/deficiência , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Transplante Homólogo
12.
Cells ; 8(3)2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917537

RESUMO

Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways.


Assuntos
Predisposição Genética para Doença , Interleucinas/metabolismo , Linfócitos/imunologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Adulto , Alelos , Estudos de Casos e Controles , Apresentação Cruzada/imunologia , Feminino , Humanos , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Fatores de Risco
13.
Allergol. immunopatol ; 47(1): 38-42, ene.-feb. 2019. graf
Artigo em Inglês | IBECS | ID: ibc-180769

RESUMO

Introduction: Disseminated BCG infections among other complications of Bacillus Calmette-Guérin (BCG) vaccine are rare and have occurred in children with immunodeficiency disorders such as mendelian susceptibility to mycobacterial disease (MSMD) which could be due to defects in some elements of IL-12/IFN-γ axis. MSMD-causing mutations have been identified in 10 genes during the last two decades. Among them, mutations in the IL12Rβ1 and IFN gamma R1 genes constitute about 80% of recorded cases of MSMD syndrome. The aim of this study was to investigate IL-12RBeta1 and IFN- gammaR1 deficiencies in patients with disseminated BCG infection. Methods: This study was performed on 31 children with disseminated BCG infections who referred to children's medical center. Whole blood cell culture was performed in presence of BCG, IL-12 and IFN- gamma stimulators. The supernatants were assayed for IFN-gamma and IL-12p70 by ELISA method. In order to evaluate IL12Rbeta1 and IFN- gammaR1 receptors expression, flow cytometry staining was performed on the patients’ T-cells stimulated with PHA. Results: Flow cytometry staining of 31 Iranian patients with disseminated BCG infections with the average age of 43 months showed lack of the expression of IL-12RBeta1 and IFN- gamma R1 genes in PHA-T-cells of the nine and one patients, respectively in whom the incomplete production of IFN- gamma and IL-12 was reported by ELISA. Among these 10 patients, eight cases had related parents (80%). Conclusion: It is recommended that to avoid BCG complications, screening be performed for MSMD before BCG inoculation in individuals with positive family history of primary immunodeficiency diseases and inhabitants of areas with high frequency of consanguinity


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Vacina BCG/imunologia , Síndromes de Imunodeficiência/epidemiologia , Mutação/genética , Infecções por Mycobacterium/epidemiologia , Receptores de Interferon/genética , Interleucina-12/genética , Linfócitos T/imunologia , Células Cultivadas , Predisposição Genética para Doença , Imunização , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Interferon gama/metabolismo , Interleucina-12/metabolismo , Irã (Geográfico)/epidemiologia , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia
14.
J Immunol ; 202(4): 1045-1056, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30617225

RESUMO

Contact hypersensitivity (CHS) is a CD8 T cell-mediated response to hapten skin sensitization and challenge. Sensitization of wild-type (WT) mice induces hapten-reactive effector CD8 T cells producing IFN-γ and IL-17- and IL-4-producing CD4 T cells that cannot mediate CHS. Although CXCR2-dependent Ly6G+ (neutrophil) cell recruitment into hapten-challenged skin is required to direct effector CD8 T cell infiltration into the challenge site to elicit CHS, 2,4-dinitrofluorobenezene (DNFB) sensitization of CXCR2-/- mice and neutrophil-depleted WT mice induced both hapten-reactive CD4 and CD8 T cells producing IFN-γ and IL-17. CD4 T cell-mediated CHS responses were not generated during DNFB sensitization of neutrophil-depleted WT mice treated with anti-IL-12 mAb or neutrophil-depleted IL-12-/- mice. Neutrophil depletion during DNFB sensitization of WT mice markedly increased IL-12-producing hapten-primed dendritic cell numbers in the skin-draining lymph nodes. Sensitization of mice lacking the neutrophil serine protease cathepsin G (CG)-induced hapten-reactive CD4 and CD8 T cells producing IFN-γ and IL-17 with elevated and elongated CHS responses to DNFB challenge. Induction of CHS effector CD4 T cells producing IFN-γ in neutrophil-depleted WT mice was eliminated by s.c. injection of active, but not inactivated, CG during sensitization. Thus, hapten skin sensitization induces neutrophil release of CG that systemically inhibits hapten-presenting dendritic cell production of IL-12 and the development of hapten-reactive CD4 T cells to IFN-γ-producing CHS effector cells.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Catepsina G/metabolismo , Células Dendríticas/metabolismo , Haptenos/metabolismo , Interleucina-12/biossíntese , Neutrófilos/enzimologia , Pele/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Dermatite de Contato/imunologia , Dermatite de Contato/metabolismo , Feminino , Haptenos/imunologia , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Receptores de Interleucina-8B/deficiência , Receptores de Interleucina-8B/imunologia , Receptores de Interleucina-8B/metabolismo , Pele/imunologia
15.
PLoS Pathog ; 15(1): e1007456, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608984

RESUMO

Innate CD8+ T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8+ T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, the thymus experiences an enrichment of single positive CD8 (SP8) thymocytes that share all the established phenotypical and functional characteristics of innate CD8+ T cells. Moreover, through in vivo experiments, we demonstrate a significant increase in survival and a lower parasitemia in mice adoptively transferred with SP8 thymocytes from OT I-T. cruzi-infected mice, demonstrating that innate CD8+ thymocytes are able to protect against a lethal T. cruzi infection in an Ag-independent manner. Interestingly, we obtained similar results when using thymocytes from systemic IL-12 + IL-18-treated mice. This data indicates that cytokines triggered during the acute stage of a Th1 infectious process induce thymic production of IL-4 along with IL-15 expression resulting in an adequate niche for development of innate CD8+ T cells as early as the double positive (DP) stage. Our data demonstrate that the thymus can sense systemic inflammatory situations and alter its conventional CD8 developmental pathway when a rapid innate immune response is required to control different types of pathogens.


Assuntos
Interleucina-15/metabolismo , Interleucina-4/metabolismo , Timo/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Feminino , Imunidade Inata/genética , Interleucina-12/metabolismo , Interleucina-15/genética , Interleucina-18/metabolismo , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Transdução de Sinais , Células Th1/imunologia , Timócitos/metabolismo , Timo/metabolismo , Timo/patologia
16.
Poult Sci ; 98(5): 2008-2013, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597054

RESUMO

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a primary avian pathogen responsible for severe intestinal pathology in younger chickens and economic losses to poultry industry. Furthermore, S. Typhimurium is also able to cause infection in humans, characterized by acute gastrointestinal disease. A study was conducted to investigate antibody response and expression kinetics of interferon gamma (IFNγ), interleukin (IL-12, and IL-18) genes in broiler chicken at 0, 1, 3, 5, 7, 9, 11, 13, and 15 D post infection following experimental infection of S. Typhimurium. Immunological studies showed higher titres of IgG and IgM in the infected group as compared to the age-matched un-infected control group. The Real-Time PCR-based gene expression analysis revealed significant increase of IFNγ, IL-12, and IL-18 mRNA levels in the infected group as compared to their respective controls (P < 0.05). The present study shall help in understanding the immune responses in birds, thus allowing development of more effective vaccines and vaccination strategies.


Assuntos
Galinhas , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/imunologia , Salmonelose Animal/genética , Salmonelose Animal/imunologia , Salmonella typhimurium/fisiologia , Animais , Anticorpos Antibacterianos/sangue , Formação de Anticorpos , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica/veterinária , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Doenças das Aves Domésticas/microbiologia , RNA Mensageiro/genética , Salmonelose Animal/microbiologia
17.
BMC Res Notes ; 12(1): 52, 2019 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674337

RESUMO

OBJECTIVE: Macrophages and dendritic cells (DCs) play key role in the recognition of mycobacterial infection and mounting of antimycobacterial immunity. In case of macrophages, recognition of BCG and other mycobacteria has been attributed predominantly to MyD88-dependent singling. Interestingly, in previous study with bone marrow-derived DCs, we have shown that BCG promotes the survival of wild-type and MyD88-/- cells to the comparable levels. In the present study, we further examined MyD88-/- DC's response to BCG. RESULTS: Bone marrow-derived DCs from wild-type and MyD88-/- mice were stimulated with BCG and analyzed for cytokine secretion. As expected, BCG-stimulated wild-type DCs produced significant amount of TNF-α and IL-12p40 in response to BCG. Interestingly, BCG-stimulated MyD88-/- DCs were also found to secret significantly higher levels of TNF-α and IL-12p40, compared with unstimulated DCs. We further observed that wild-type DCs produced significant level of immunosuppressive cytokine IL-10 in response to BCG, whereas MyD88-/- DCs secreted very low amount of IL-10 when stimulated with BCG. These findings demonstrated that MyD88-/- DCs exhibit a skewed cytokine response to BCG.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Mycobacterium bovis , Fator 88 de Diferenciação Mieloide/deficiência , Fator de Necrose Tumoral alfa/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
Virology ; 529: 65-72, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30665099

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) infects monocyte-derived DCs, and previous reports have shown that PRRSV does not infect conventional DCs (cDCs) in vitro, but the effects on cDCs from lymphoid tissues are unknown. This study analyzed the response and susceptibility of tonsil DEC205+cDCs from infected pigs. We confirmed the phenotype and lineage of bona fide tonsil cDCs with the mRNA expression of FLT3+ and the phenotype MHCII+CADM1highDEC205+ (DEC205+cDCs). These cells were not infected by PRRSV, whereas CD163+ tonsil cells were infected. The numbers of tonsil cDCs and CD163+ cells were not affected by PRRSV, in contrast to the reduction in alveolar macrophage numbers. DEC205+cDCs exhibited an increase in the expression of IL-12 at 5 days postinfection, suggesting a proinflammatory response by these cells to the virus. In summary, this study confirms that, in vitro and in vivo, cDCs are not susceptible to PRRSV but can respond against it.


Assuntos
Células Dendríticas/virologia , Tonsila Palatina/citologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Molécula 1 de Adesão Celular/genética , Molécula 1 de Adesão Celular/metabolismo , Regulação da Expressão Gênica/imunologia , Interleucina-12/genética , Interleucina-12/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Complexo Principal de Histocompatibilidade , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/metabolismo , Síndrome Respiratória e Reprodutiva Suína/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Suínos , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
19.
Genes Immun ; 20(3): 181-197, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29599514

RESUMO

Human IL12RB1 is an autosomal gene that is essential for mycobacterial disease resistance and T cell differentiation. Using primary human tissue and PBMCs, we demonstrate that lung and T cell IL12RB1 expression is allele-biased, and the extent to which cells express one IL12RB1 allele is unaffected by activation. Furthermore following its expression the IL12RB1 pre-mRNA is processed into either IL12RB1 Isoform 1 (IL12Rß1, a positive regulator of IL12 responsiveness) or IL12RB1 Isoform 2 (a protein of heretofore unknown function). T cells choice to process pre-mRNA into Isoform 1 or Isoform 2 is controlled by intragenic competition of IL12RB1 exon 9-10 splicing with IL12RB1 exon 9b splicing, as well as an IL12RB1 exon 9b-associated polyadenylation site. Heterogeneous nuclear ribonucleoprotein H (hnRNP H) binds near the regulated polyadenylation site, but is not required for exon 9b polyadenylation. Finally, microRNA-mediated knockdown experiments demonstrated that IL12RB1 Isoform 2 promotes T cell IL12 responses. Collectively, our data support a model wherein tissue expression of human IL12RB1 is allele-biased and produces an hnRNP H-bound pre-mRNA, the processing of which generates a novel IL12 response regulator.


Assuntos
Alelos , Interleucina-12/genética , Processamento de RNA , Receptores de Interleucina-12/genética , Células Cultivadas , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Humanos , Interleucina-12/metabolismo , Células Jurkat , Pulmão/metabolismo , Ligação Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Interleucina-12/metabolismo , Linfócitos T/metabolismo
20.
Microb Pathog ; 126: 63-73, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30366126

RESUMO

The capacity of Mycobacterium tuberculosis to survive and cause disease is strongly correlated with its ability to escape multiple defense strategies in hosts. In particular, M. tuberculosis has the remarkable capacity to survive within the hostile environment of macrophages. Here, we found that the PE17 (Rv1646) protein promoted intracellular survival of M. smegmatis in peritoneal macrophages from mice. Further experiments confirmed that the recombinant PE17 protein was localized in the cell wall of M. smegmatis. Results from the macrophage infection model showed that PE17 significantly downregulated pro-inflammatory cytokines (interleukin-6, interleukin-12, and tumer necrosis factor-α) secretion from macrophages induced by M. smegmatis and promoted macrophage necrosis. Furthermore, a C57BL/6 mouse infection model confirmed that PE17 significantly prolonged the survival of M. smegmatis in vivo and aggravated lesions in organs of infected mice. Moreover, persistent high levels of interferon-γ and interleukin-1ß in infected mice indicated that the bacteria were not easily removed in vivo. Overall, our present results suggested that the PE17 may act as an important pathogenic factor in M. tuberculosis.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium smegmatis/metabolismo , Mycobacterium tuberculosis/metabolismo , Fatores de Virulência/metabolismo , Animais , Antígenos de Bactérias/genética , Apoptose , Proteínas de Bactérias/genética , Morte Celular , Parede Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação Bacteriana da Expressão Gênica , Interações Hospedeiro-Patógeno , Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim/microbiologia , Rim/patologia , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , Infecções por Micobactéria não Tuberculosa/microbiologia , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Proteínas Recombinantes , Baço/microbiologia , Baço/patologia , Fator de Necrose Tumoral alfa/metabolismo , Virulência , Fatores de Virulência/genética
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