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1.
N Engl J Med ; 382(3): 256-265, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31940699

RESUMO

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).


Assuntos
Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Interferons/metabolismo , Interleucinas/metabolismo , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Mutação com Perda de Função , Pirazóis/uso terapêutico , Ubiquitina Tiolesterase/deficiência , Homozigoto , Humanos , Hidrocefalia/genética , Recém-Nascido , Masculino , Receptores de Interferon/metabolismo , Indução de Remissão , Choque Séptico/genética , Transdução de Sinais/genética , Ubiquitina Tiolesterase/genética , Sequenciamento Completo do Exoma
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(8): 744-749, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31638572

RESUMO

Objective To demonstrate HpaA can intensify the inflammatory response and gastric mucosa injury by IL-21 from induced T cell. Methods Biopsy specimens were taken from gastric mucosa of 56 patients with H.pylori infection before and after H.pylori radical elimination by endoscope. The levels of IL-21, matrix metalloproteinase-2 (MMP2) and MMP9 from the biopsy were detected by reverse transcription PCR and Western blot analysis. Meanwhile, the recombinant HpaA was cloned, expressed and purified to stimulate the magnetic cell sorting CD3+ T cells from healthy donors' peripheral blood mononuclear cells (PBMCs), and the level of IL-21 in the supernatant fluid was detected by ELISA. Thereafter, AGS cells were cultured and Western blot analysis was performed to detect the levels of MMP2 and MMP9 in the AGS cells with human IL-21 and anti-IL-21 antibody treatment for 24 hours. Results The protein levels of IL-21 and MMP2 and MMP9 in gastric mucosa infected with H. pylori was significantly higher than that in gastric mucosa after radical treatment of H. pylori. Meanwhile, the recombinant HpaA promoted IL-21 secretion by induced CD3+T cells in vitro. IL-21 stimulated the expression of MMP2 and MMP9 in AGS cells. When IL-21 was blocked by the antibody, the levels of MMP2 and MMP9 in AGS cells decreased significantly. Conclusion HpaA plays a significant role in the gastric mucosa injury caused by H.pylori infection through IL-21 from induced T cells.


Assuntos
Adesinas Bacterianas , Mucosa Gástrica , Interleucinas , Linfócitos T , Adesinas Bacterianas/metabolismo , Mucosa Gástrica/lesões , Mucosa Gástrica/fisiopatologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Humanos , Interleucinas/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Linfócitos T/metabolismo
3.
Nat Commun ; 10(1): 4601, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601798

RESUMO

During pregnancy, trophoblast cells sustain the maternal-fetal tolerance via expressing and secreting various chemokines and cytokines. Our previous study revealed the expression of interleukin-35 (IL-35) in human first-trimester trophoblasts. Here we show that IL-35 is expressed in both human first-trimester primary trophoblast cells and a trophoblast cell line. Trophoblast cells inhibit the proliferation of human naive conventional T cells (Tconv cells) and convert suppressed Tconv cells into iTR35 in an IL-35-dependent manner. Mechanistically, trophoblast cell derived IL-35 mediates its function through phosphorylation of STAT1 and STAT3. In vivo studies confirm that mice with immunologically spontaneous abortion have lower levels of IL-35 and iTR35 cells at the maternal-fetal interface, and neutralizing anti-IL-35 mAb enhances abortion rates. Meanwhile, exogenous IL-35 induces iTR35 and prevents immunological abortion. Our findings thus suggest that trophoblast cells have a critical function in preserving maternal-fetal tolerance via secreting IL-35 during pregnancy.


Assuntos
Interleucinas/metabolismo , Troca Materno-Fetal/fisiologia , Linfócitos T Reguladores/imunologia , Trofoblastos/citologia , Animais , Proliferação de Células , Feminino , Humanos , Tolerância Imunológica , Interleucinas/sangue , Interleucinas/imunologia , Interleucinas/farmacologia , Masculino , Troca Materno-Fetal/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Placenta/citologia , Placenta/imunologia , Gravidez , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Trofoblastos/imunologia , Trofoblastos/metabolismo
4.
Cell Prolif ; 52(6): e12703, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31621133

RESUMO

OBJECTIVES: Interleukin-34 (IL-34) is associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, the role and associated mechanisms of IL-34 in HBV-related HCC remain unclear. In this study, the expression, biological function and associated mechanisms of IL-34 in HBV-related HCC cells were investigated. METHODS: IL-34 expression induced by HBV and HBV X (HBX) gene was measured in hepatoma cells. The role of CCAAT/enhancer-binding protein α (CEBP/α) in HBX-induced IL-34 expression was examined. The signal pathways involved in the expression of CEBP/α and IL-34 induced by HBX were assessed. The role of IL-34 in the proliferation and migration of HCC cells, and related mechanisms were explored. RESULTS: Dependent on HBX, HBV increased IL-34 expression in hepatoma cells, and HBX upregulated and interacted with CEBP/α to enhance the activity of IL-34 promoters. CEBP/α mediated by HBX was associated with the activation of PI3-K and NF-κB pathways to promote IL-34 expression. Via CSF1-R and CD138, IL-34 promoted the proliferation and migration of hepatoma cells, and contributed to the activation of ERK and STAT3 pathways and the upregulation of Bcl-xl and c-Myc mediated by HBX. CONCLUSION: We demonstrate that IL-34 contributes to HBX-mediated functional abnormality of HCC cells and provides a novel insight into the molecular mechanism of carcinogenesis mediated by HBX.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Interleucinas/metabolismo , Transativadores/metabolismo , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Hepatite B , Humanos , Neoplasias Hepáticas/genética
5.
APMIS ; 127(12): 789-796, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31512766

RESUMO

The aim was to examine anti-tumor necrosis factor α (anti-TNFα) therapy influence changes on Th17 and Th22 cells in patients with spondyloarthritis (SpA), and its correlation with changes in clinical and magnetic resonance imaging (MRI) activity and chronicity scores. The Th17 and Th22 cells were assessed at baseline, after 12 and 52 weeks of anti-TNFα therapy by flow cytometry (ClinicalTrials.gov NCT4682724). The percentages of both Th17 and Th22 cells were increased by 70% at baseline compared with healthy controls (both p < 0.01). During treatment, these two subsets increased further to be 170% (Th17) and 123% (Th22) above levels in healthy controls (both p < 0.01). The same subsets decrease their expression of IL-23R significantly during the observation period (p < 0.05). High levels of Th17 and Th22 cells at baseline were associated with the degree of chronic changes in the sacroiliac joints on MRI and a good clinical response to anti-TNFα treatment after one year. Plasma levels were not associated with clinical changes. Th17 cells, and Th22 subsets, increased during one year of anti-TNF-α therapy in SpA, regardless of their clinical improvement. This supports that both the Th17 and Th22 subsets could be involved in the progression in SpA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Espondilartrite/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anti-Inflamatórios/farmacologia , Feminino , Citometria de Fluxo , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Espondilartrite/diagnóstico por imagem , Espondilartrite/imunologia , Espondilartrite/patologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Resultado do Tratamento
6.
Gastroenterology ; 157(6): 1584-1598, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513797

RESUMO

BACKGROUND & AIMS: T-regulatory (Treg) cells suppress the immune response to maintain homeostasis. There are 2 main subsets of Treg cells: FOXP3 (forkhead box protein 3)-positive Treg cells, which do not produce high levels of effector cytokines, and type 1 Treg (Tr1) cells, which are FOXP3-negative and secrete interleukin (IL) 10. IL10 is an anti-inflammatory cytokine, so Tr1 cells might be used in the treatment of inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions. METHODS: We obtained blood and colon biopsy samples from patients with Crohn's disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples and stimulated with anti-CD3 and anti-CD28 beads, and Tr1 cells were purified by using an IL10 cytokine-capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3 and anti-CD28 beads, and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colon organoid cultures were established, cultured with supernatants from Tr1 or FOXP3-positive cells, and analyzed by immunofluorescence and flow cytometry. T84 cells (human colon adenocarcinoma epithelial cells) were incubated with supernatants from Tr1 or FOXP3-positive cells, and transepithelial electrical resistance was measured to determine epithelial cell barrier function. RESULTS: Phenotypes of Tr1 cells isolated from control individuals vs patients with Crohn's disease or ulcerative colitis did not differ significantly after expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1B and tumor necrosis factor from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy individuals and patients with Crohn's disease or ulcerative colitis secreted IL22, which promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures. CONCLUSIONS: Human Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (inmate immune response). They also secrete IL22 to promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.


Assuntos
Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , Interleucina-10/metabolismo , Mucosa Intestinal/patologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Biópsia , Comunicação Celular/imunologia , Proliferação de Células , Células Cultivadas , Colite Ulcerativa/sangue , Colite Ulcerativa/terapia , Colo/citologia , Colo/imunologia , Colo/patologia , Doença de Crohn/sangue , Doença de Crohn/terapia , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Voluntários Saudáveis , Humanos , Interleucina-10/imunologia , Interleucinas/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante
7.
Med Sci Monit ; 25: 6523-6531, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31471534

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS) in infants is acute and progressive hypoxic respiratory failure caused by various extrapulmonary pathogenic factors besides cardiogenic factors. Diffuse alveolar injury and progression to pulmonary fibrosis are pathological features of ARDS. The present study sought to determine how puerarin influences the inflammatory response caused by pulmonary fibrosis in ARDS in infants. MATERIAL AND METHODS The human lung fibroblasts cell line HLF1 was treated with different concentrations of puerarin in different groups for various times. TGF-ß1 was overexpressed by TGF-ß1 (2 ng/mL) in routine experiments, and the treated cells and culture supernatant were collected for analysis in each step. Cell apoptosis was measured by flow cytometry, TUNEL assay, and detection of caspase 3 and Bcl-2. Cell proliferation was assessed by CCK-8 assay. Real-time PCR and Western blot assay were used to assess mRNA and protein levels of TGF-ß1 and Smad3, respectively. The related cytokines were assessed by ELISA. RESULTS Results showed that puerarin promoted the apoptosis and inhibited the proliferation of HLF1 cells. Caspase 3 was upregulated, whereas Bcl-2, TGF-ß1, and Smad3 were downregulated by puerarin. IL-1, IL-2, and IL-4, secreted by HLF1 cells, were reduced, but IL-10 showed the opposite trend. When TGF-ß1 was overexpressed, Smad3 was promoted, and IL-1, IL-2, and IL-4 was increased in HLF1 cells. Finally, overexpression of TGF-ß1 reversed the effect of puerarin in HLF1 cells. CONCLUSIONS Puerarin regulated the proliferation and apoptosis of pulmonary fibrosis cells, and affected the secretion of inflammatory cytokines. Thus, puerarin alleviated the inflammatory response resulting from pulmonary fibrosis by regulating the TGF-ß1/Smad3 pathway in infants with ARDS.


Assuntos
Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Inflamação/patologia , Interleucinas/metabolismo , Isoflavonas/farmacologia , Pulmão/embriologia , Pulmão/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/patologia
8.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480263

RESUMO

The aim of this study was to investigate possible stress-associated disturbances in lipid metabolism in mononuclear cells, mainly lymphocytes of patients with psoriasis vulgaris (Ps, n = 32) or with psoriatic arthritis (PsA, n = 16) in respect to the healthy volunteers (n = 16). The results showed disturbances in lipid metabolism of psoriatic patients reflected by different phospholipid profiles. The levels of non-enzymatic lipid metabolites associated with oxidative stress 8-isoprostaglandin F2α (8-isoPGF2α) and free 4-hydroxynonenal (4-HNE) were higher in PsA, although levels of 4-HNE-His adducts were higher in Ps. In the case of the enzymatic metabolism of lipids, enhanced levels of endocannabinoids were observed in both forms of psoriasis, while higher expression of their receptors and activities of phospholipases were detected only in Ps. Moreover, cyclooxygenase-1 (COX-1) activity was enhanced only in Ps, but cyclooxygenase-2 (COX-2) was enhanced both in Ps and PsA, generating higher levels of eicosanoids: prostaglandin E1 (PGE1), leukotriene B4 (LTB4), 13-hydroxyoctadecadienoic acid (13HODE), thromboxane B2 (TXB2). Surprisingly, some of major eicosanoids 15-d-PGJ2 (15-deoxy-Δ12,14-prostaglandin J2), 15-hydroxyeicosatetraenoic acid (15-HETE) were elevated in Ps and reduced in PsA. The results of our study revealed changes in lipid metabolism with enhancement of immune system-modulating mediators in psoriatic mononuclear cells. Evaluating further differential stress responses in Ps and PsA affecting lipid metabolism and immunity might be useful to improve the prevention and therapeutic treatments of psoriasis.


Assuntos
Artrite Psoriásica/sangue , Artrite Psoriásica/metabolismo , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos , Psoríase/sangue , Psoríase/metabolismo , Adulto , Eicosanoides/metabolismo , Endocanabinoides/metabolismo , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Interleucinas/metabolismo , Masculino , Oxirredução , Fosfolipídeos/metabolismo , Análise de Componente Principal
9.
J Med Food ; 22(10): 1067-1077, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31403348

RESUMO

To reduce microbial loads in medicinal herbs, Cnidii Rhizoma and Alismatis Rhizoma were subjected to electron-beam (e-beam) irradiation at doses (≤10 kGy) as permitted by the Korean Food Code. The effects of e-beam irradiation on the microbial load, stability of the active components, and anti-inflammatory activity of medicinal herbs were determined. We observed that the total aerobic bacteria (TAB; 4.0-7.0 log CFU/g), yeasts and molds (Y&M; 3.3-6.8 log CFU/g), and coliform counts (CC; 3.2-3.8 log CFU/g) in both herb samples were effectively reduced in a dose-dependent manner, resulting in acceptable levels of <3.0 log CFU/g in TAB and Y&M and negative in CC at 10 kGy irradiation. The concentration of the active components (0.87-4.22 mg/g) of Cnidii Rhizoma, including z-ligustilide, chlorogenic acid, senkyunolide A, and ferulic acid, in order of prevalence and those (0.86-2.76 mg/g) of Alismatis Rhizoma, including Alisol B acetate and Alisol B, were not changed at irradiation doses of ≤10 kGy. The extracts of e-beam irradiated Cnidii Rhizoma and Alismatis Rhizoma showed a reduced production of inflammation-related factors, such as nitric oxide, prostaglandin E2, interleukin (IL)-1ß, and IL-6, in a concentration-dependent manner, which was induced by lipopolysaccharide in RAW 264.7 cell. However, there was no significant difference observed at e-beam irradiation doses of 0, 1, 5, and 10 kGy. Thus, we confirm that e-beam irradiation up to 10 kGy was effective for the control of microbial load in Cnidii Rhizoma and Alismatis Rhizoma without causing considerable changes in their major active components and anti-inflammatory activity. The results show the potential of e-beam application for sanitization of medicinal herbs.


Assuntos
Alisma/química , Anti-Inflamatórios/química , Apiaceae/química , Carga Bacteriana , Rizoma/química , Alisma/microbiologia , Alisma/efeitos da radiação , Animais , Anti-Inflamatórios/farmacologia , Apiaceae/microbiologia , Apiaceae/efeitos da radiação , Dinoprostona/metabolismo , Elétrons , Interleucinas/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Plantas Medicinais/química , Plantas Medicinais/microbiologia , Plantas Medicinais/efeitos da radiação , Células RAW 264.7 , Rizoma/microbiologia , Rizoma/efeitos da radiação
10.
Zygote ; 27(5): 285-298, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31412964

RESUMO

Ovulation is considered an inflammatory, cytokine-mediated event. Cytokines, which are recognized as growth factors with immunoregulatory properties, are involved in many cellular processes at the ovarian level. In this sense, cytokines affect fertility and are involved in the development of different ovarian disorders such as bovine cystic ovarian disease (COD). Because it has been previously demonstrated that ovarian cells represent both sources and targets of cytokines, the aim of this study was to examine the expression of several cytokines, including IL-1ß, IL-1RA, IL-1RI, IL-1RII, IL-4 and IL-8, in ovarian follicular structures from cows with spontaneous COD. The protein expression of these cytokines was evaluated by immunohistochemistry. Additionally, IL-1ß, IL-4 and IL-8 concentrations in follicular fluid (FF) and serum were determined by enzyme-linked immunosorbent assay (ELISA). In granulosa and theca cells, IL-1RI, IL-1RII, IL-1RA and IL-4 expression levels were higher in cystic follicles than in the control dominant follicles. The serum and FF concentrations of IL-1ß and IL-4 showed no differences between groups, whereas IL-8 concentration was detected only in FF of cysts from cows with COD. The FF and serum concentrations of IL-1ß and IL-8 showed no significant differences, whereas IL-4 concentration was higher in FF than in serum in both the control and COD groups. These results evidenced an altered expression of cytokines in ovaries of cows with COD that could contribute to the pathogenesis of this disease.


Assuntos
Líquido Folicular/metabolismo , Interleucinas/metabolismo , Cistos Ovarianos/metabolismo , Cistos Ovarianos/patologia , Animais , Estudos de Casos e Controles , Bovinos , Doenças dos Bovinos , Feminino , Proteína Antagonista do Receptor de Interleucina 1/sangue , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/sangue , Interleucina-4/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Cistos Ovarianos/veterinária , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo II de Interleucina-1/metabolismo
11.
Infect Immun ; 87(11)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31383743

RESUMO

Interleukin-21 (IL-21), a cytokine produced by many subsets of activated immune cells, is critical for driving inflammation in several models. Using Helicobacter pylori infection as a model for chronic mucosal infection, we previously published that IL-21 is required for the development of gastritis in response to infection. Concomitant with protection from chronic inflammation, H. pylori-infected IL-21-/- mice exhibited limited Th1 and Th17 responses in their gastric mucosa. Here we report that H. pylori-infected IL-21-/- mice express significantly higher levels of IL-17A than H. pylori-infected wild-type (WT) mice in the Peyer's patches and mesenteric lymph nodes. This led us to hypothesize that IL-21 may indirectly regulate H. pylori-specific T cell responses by controlling dendritic cell (DC) functions in mucosa-associated lymphoid tissue. It was found that IL-21 treatment reduced the ability of dendritic cells to produce proinflammatory cytokines in response to H. pylori While H. pylori increased the expression of costimulatory proteins on DCs, IL-21 reduced the expression of CD40 in the presence of H. pylori Also, Th17 recall responses were intact when DCs were used as antigen-presenting cells in the presence of IL-21, but IL-21 did impact the ability of DCs to induce antigen-specific proliferation. These data suggest that IL-21, while proinflammatory in most settings, downregulates the proinflammatory cytokine microenvironment through modulating the cytokine expression of DCs, indirectly modifying IL-17A expression. Understanding how these proinflammatory cytokines are regulated will advance our understanding of how and why H. pylori infection may be tolerated in some individuals while it causes gastritis, ulcers, or cancer in others.


Assuntos
Citocinas/metabolismo , Células Dendríticas/fisiologia , Helicobacter pylori/fisiologia , Interleucina-17/metabolismo , Interleucinas/metabolismo , Linfócitos T/metabolismo , Animais , Citocinas/genética , Células Dendríticas/microbiologia , Feminino , Regulação da Expressão Gênica/fisiologia , Infecções por Helicobacter , Interleucina-17/genética , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nódulos Linfáticos Agregados/metabolismo
12.
BMC Infect Dis ; 19(1): 745, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455239

RESUMO

BACKGROUND: Due to the similar clinical, lung imaging, and pathological characteristics, talaromycosis is most commonly misdiagnosed as tuberculosis. This study aimed to identify the characteristics of talaromycosis pleural effusion (TMPE) and to distinguish TMPE from tuberculosis pleural effusion (TPE). METHODS: We enrolled 19 cases each of TMPE and TPE from Guangxi, China. Patients' clinical records, pleural effusion tests, biomarker test results, and receiver operating characteristic curves were analyzed. RESULTS: In total, 39.8% (65/163) of patients exhibited serous effusion, of whom 61 were non-human immunodeficiency virus (HIV)-infected patients; 68.85% of the non-HIV-infected patients (42/61) had TMPE. Thoracentesis was performed only in 19 patients, all of whom were misdiagnosed with tuberculosis and received long-term anti-tuberculosis treatment. In four of these patients, interleukin (IL)-23, IL-27, and interferon-gamma (IFN-γ) measurements were not performed since pleural effusion samples could not be collected because the effusion had been drained prior to the study. In the remaining 15 patients, pleural effusion samples were collected. Talaromyces marneffei was isolated from the pleural effusion and pleural nodules. Most TMPEs were characterized by yellowish fluid, with marked elevation of protein content and nucleated cell counts. However, neutrophils were predominantly found in TMPEs, and lymphocytes were predominantly found in TPEs (both p < 0.05). Adenosine deaminase (ADA) and IFN-γ levels in TMPEs were significantly lower than those in TPEs (all p < 0.05) and provided similar accuracies for distinguishing TMPEs from TPEs. IL-23 concentration in TMPEs was significantly higher than that in TPEs (p < 0.05), and it provided similar accuracy for diagnosing TMPEs. IL-27 concentrations in TMPEs were significantly lower than those in TPEs (all p < 0.05) but was not useful for distinguishing TMPE from TPE. CONCLUSIONS: Talaromycosis can infringe on the pleural cavity via the translocation of T. marneffei into the pleural space. Nonetheless, this phenomenon is still commonly neglected by clinicians. TMPE is a yellowish fluid with exudative PEs and predominant neutrophils. Higher neutrophil counts and IL-23 may suggest talaromycosis. Higher lymphocyte counts, ADA activity, and IFN-γ concentration may suggest tuberculosis.


Assuntos
Micoses/etiologia , Derrame Pleural/microbiologia , Tuberculose Pleural/diagnóstico , Adenosina Desaminase/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Interferon gama/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Interleucinas/metabolismo , Linfócitos/microbiologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Micoses/microbiologia , Neutrófilos/microbiologia , Neutrófilos/patologia , Derrame Pleural/diagnóstico , Derrame Pleural/tratamento farmacológico , Curva ROC , Talaromyces/patogenicidade , Tuberculose Pleural/tratamento farmacológico , Tuberculose Pleural/etiologia
13.
Appl Microbiol Biotechnol ; 103(19): 7931-7941, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31456001

RESUMO

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD) characterized by superficial mucosal inflammation, rectal bleeding, diarrhea, and abdominal pain. Anti-inflammatory and immunosuppressive drugs have been used in the therapy of human UC. Interleukin (IL)-35, which functions as an anti-inflammatory cytokine, has been shown to play a potential therapeutic role in a UC-like mouse colitis induced by dextran sodium sulfate (DSS). However, the contribution of IL-35 via oral administration to colitis prevention has not been determined. In order to explore its preventative potentiality, a dairy Lactococcus lactis NZ9000 strain was engineered to express murine IL-35 (NZ9000/IL-35), and this recombinant bacteria was applied to prevent and limit the development of DSS-induced mouse colitis. We found that oral administration of NZ9000/IL-35 induced the accumulation of IL-35 in the gut lumen of normal mice. When administrated preventatively, NZ9000/IL-35-gavaged mice exhibited decreased weight loss, DAI score, colon shortening as well as colitis-associated histopathological changes in colon, indicating that the oral administration of NZ9000/35 contributed to the suppression of DSS-induced colitis progression. Moreover, much less Th17 cells and higher level of Treg cells in lamina propria, as well as increased colon and serum levels of IL-10 with a concomitant reduced pro-inflammatory cytokines, IL-6, IL-17A, IFN-γ, and TNF-α were apparently regulated by NZ9000/IL-35 in colitis mice. Together, we put forward direct evidence pinpointing the effectiveness of NZ9000/IL-35 in preventing UC-like mouse colitis, implying a potential candidate of this recombinant Lactococcus lactis that prevent the progression of IBD.


Assuntos
Colite Ulcerativa/prevenção & controle , Fatores Imunológicos/metabolismo , Interleucinas/metabolismo , Lactococcus lactis/metabolismo , Administração Oral , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Fatores Imunológicos/genética , Interleucinas/genética , Mucosa Intestinal/patologia , Lactococcus lactis/genética , Camundongos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Resultado do Tratamento
14.
Environ Sci Pollut Res Int ; 26(29): 30444-30451, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440970

RESUMO

Heavily chromium-polluted areas, where people are prohibited from entering, are paradises for stray dogs. In this study, stray dogs were used to study the effects of chromium exposure on the heart of dogs in severely Cr(VI)-contaminated rural areas of China. The dogs were given water (control), low dose (L, 0.92 mg/kg), medium dose (M, 1.15 mg/kg), and high dose (H, 1.38 mg/kg) of Cr(VI). The changes of electrocardiogram (ECG), myocardial enzyme parameters, inflammatory factors, oxidative kinase, and ATPase were measured to determine the toxicity of chromium on the heart of dogs. Results showed that the ST segment of ECG increased significantly, and the amplitude of T wave increased in the experimental group. The myocardial enzyme (CK-MB, AST, CK, and LDH) content in groups M and H increased significantly over time. The values of CAT, T-SOD, IL-10, and ATPase (K+-Na+-ATPase and Ca2+-Mg2+-ATPase) decreased with the increase of Cr(VI) dose, and the content of MDA, IL-1ß, IL-8, and TNF-α increased with the increase of Cr(VI) dose. Our study suggested that the heart of Chinese rural dog was damaged by Cr(VI), and Cr(VI) could cause oxidative damage and alteration of ATPase content in dogs.


Assuntos
Adenosina Trifosfatases/metabolismo , Cromo/toxicidade , Exposição Dietética/efeitos adversos , Coração/efeitos dos fármacos , Miocárdio/metabolismo , Animais , Animais Selvagens , Antioxidantes/metabolismo , China , Cães , Eletrocardiografia , Poluentes Ambientais/toxicidade , Interleucinas/metabolismo , Miocardite/metabolismo , Miocárdio/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
15.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434203

RESUMO

Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.


Assuntos
Células Dendríticas/metabolismo , Dermatite Atópica/metabolismo , Interleucina-4/farmacologia , Interleucinas/metabolismo , Receptores de Interleucina/metabolismo , Animais , Células Dendríticas/efeitos dos fármacos , Dermatite Atópica/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interleucina-4/uso terapêutico , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos
16.
Infect Immun ; 87(11)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31451621

RESUMO

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide, and interleukin-22 (IL-22) helps contain pneumococcal burden in lungs and extrapulmonary tissues. Administration of IL-22 increases hepatic complement 3 and complement deposition on bacteria and improves phagocytosis by neutrophils. The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22 binding protein (IL-22BP), encoded by Il22ra2 To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined. Here, we show that Il22ra2 inhibits IL-22 during S. pneumoniae lung infection and that Il22ra2 deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22-dependent manner. Il22ra2-/- mice are more resistant to S. pneumoniae infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection than control mice. Transcriptome sequencing (RNA-seq) analysis of infected Il22ra2-/- mouse lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and dendritic cells (DCs). Accordingly, we saw that macrophages from Il22ra2-/- mice displayed reduced OXPHOS gene expression upon infection with S. pneumoniae, changes that were IL-22 dependent. Furthermore, we showed that macrophages express IL-22 receptor subunit alpha-1 (IL-22Ra1) during pneumococcal infection and that Il22ra2-/- macrophages rely more on the glycolytic pathway than wild-type (WT) controls. Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.


Assuntos
Interleucinas/metabolismo , Pneumonia Pneumocócica/metabolismo , Receptores de Interleucina/metabolismo , Animais , Linhagem Celular , Suscetibilidade a Doenças , Células Epiteliais/fisiologia , Regulação da Expressão Gênica , Interleucinas/genética , Antígenos Comuns de Leucócito , Pulmão/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Oxirredução , Fosforilação , Pneumonia Pneumocócica/imunologia , Receptores de Interleucina/genética , Streptococcus pneumoniae
17.
Gastroenterology ; 157(5): 1310-1322.e13, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31352002

RESUMO

BACKGROUND & AIMS: Interferon lambda (IFNL) is expressed at high levels by intestinal epithelial cells (IECs) and mucosal immune cells in response to infection and inflammation. We investigated whether IFNL might contribute to pathogenesis of Crohn's disease (CD). METHODS: We obtained serum samples and terminal ileum biopsies from 47 patients with CD and 16 healthy individuals (controls). We measured levels of IFNL by enzyme-linked immunosorbent assay and immunohistochemistry and location of expression by confocal microscopy. Activation of IFNL signaling via STAT1 was measured in areas of no, mild, moderate, and severe inflammation and correlated with Paneth cell homeostasis and inflammation. IFNL expression and function were studied in wild-type mice and mice with intestinal epithelial cell-specific (ΔIEC) disruption or full-body disruption of specific genes (Mlkl-/-, Stat1ΔIEC, Casp8ΔIEC, Casp8ΔIECRipk3-/-, Casp8ΔIECTnfr-/-, Casp8ΔIECMlkl-/-, and Nod2-/- mice). Some mice were given tail vein injections of a vector encoding a secreted form of IFNL. Intestinal tissues were collected from mice and analyzed by immunohistochemistry and immunoblots. We generated 3-dimensional small intestinal organoids from mice and studied the effects of IFNL and inhibitors of STAT-signaling pathway. RESULTS: Patients with CD had significant increases in serum and ileal levels of IFNL compared with controls. Levels of IFNL were highest in ileum tissues with severe inflammation. High levels of IFNL associated with a reduced number of Paneth cells and increased cell death at the crypt bottom in inflamed ileum samples. Intestinal tissues from the ileum of wild-type mice injected with a vector expressing IFNL had reduced numbers of Paneth cells. IFNL-induced death of Paneth cells in mice did not occur via apoptosis, but required Mixed Lineage Kinase Domain Like (MLKL) and activation of Signal transducer and activator of transcription 1 (STAT1). In organoids, inhibitors of Janus kinase (JAK) signaling via STAT1 (glucocorticoids, tofacitinib, or filgotinib) reduced expression of proteins that mediate cell death and prevented Paneth cell death. CONCLUSIONS: Levels of IFNL are increased in serum and inflamed ileal tissues from patients with CD and associated with a loss of Paneth cells. Expression of a secreted form of IFNL in mice results in loss of Paneth cells from intestinal tissues, via STAT1 and MLKL, controlled by caspase 8. Strategies to reduce IFNL or block its effects might be developed for treatment of patients with CD affecting the terminal ileum.


Assuntos
Doença de Crohn/metabolismo , Íleo/metabolismo , Interferons/metabolismo , Interleucinas/metabolismo , Celulas de Paneth/metabolismo , Fator de Transcrição STAT1/metabolismo , Animais , Caspase 8/genética , Caspase 8/metabolismo , Morte Celular , Doença de Crohn/imunologia , Doença de Crohn/patologia , Modelos Animais de Doenças , Humanos , Íleo/imunologia , Íleo/patologia , Interferons/genética , Interleucinas/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Celulas de Paneth/imunologia , Celulas de Paneth/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Fator de Transcrição STAT1/deficiência , Fator de Transcrição STAT1/genética , Transdução de Sinais , Técnicas de Cultura de Tecidos , Regulação para Cima
18.
Eur J Med Res ; 24(1): 24, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331400

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T-cell-dependent B-cell activation and altered T-cell response. Co-stimulatory and co-inhibitory molecules regulate and exert T-cell differentiation, survival and cytokine production. CD134+ and PD-1+ T-cells in SLE patients are increased in SLE. The aim of this study was to characterize CD134+ and PD-1+CD4+ T-cells according to their ability to produce IFN-γ, IL-21 and IL-22 in SLE patients. METHODS: Peripheral blood of 39 SLE patients and 19 healthy controls (HC) was stimulated with phorbol myristate acetate (PMA) calcium ionophore (Ca-Io). The expression of IFN-γ, IL-21 and IL-22 T-cells within the CD134+ and PD-1+ T-cells was analyzed by flow cytometry. Disease activity was assessed by SLE Disease Activity Index. RESULTS: Peripheral unstimulated CD134+ and PD-1+ CD4+ T-cells were significantly increased in patients with lupus nephritis. Upon stimulation both, CD134+ and PD-1+ CD4+ T-cells, produced significantly less IFN-γ in SLE patients as compared to HC. The percentages of IL-22 within the CD134+CD4+ T-cells were also significantly decreased in SLE as compared to HC. CONCLUSION: CD134+ and PD-1+CD4+ T-cells have mainly a Th1 effector T-cell signature. A lower proportion produces also IL-21 and IL-22. The impaired capacity to produce IFN-γ and IL-22 in SLE patients may contribute to the pathogenesis of the disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucinas/biossíntese , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ionóforos de Cálcio/farmacologia , Estudos de Casos e Controles , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Interferon gama/metabolismo , Interleucinas/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/imunologia , Masculino , Acetato de Tetradecanoilforbol/farmacologia
19.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311100

RESUMO

The interleukin (IL)-20 subfamily of cytokines consists of IL-19, IL-20, IL-22, IL-24, and IL-26, and the expression of IL-20, IL-22, and IL-24 is reported to be higher in the colon of patients with ulcerative colitis. Although the receptors for these cytokines are highly expressed in the colon epithelium, their effects on epithelial renewal are not clearly understood. This study evaluated the effects of IL-20, IL-22, and IL-24 in epithelial renewal using the LS174T human colon cancer epithelial cell line. LS174T cells were treated with IL-20, IL-22, and IL-24 (25, 50, and 100 ng/mL) and a live-cell imaging system was used to evaluate the effects on cell proliferation. Following treatment, the signaling pathways contributing to cell proliferation were investigated through Western blotting in LS174T cells and downstream transcriptional changes through qRT-PCR in LS174T cells, and RNA-Seq in primary murine intestinal epithelial cells. Our results demonstrated that only IL-22 promoted LS174T cell proliferation, mediated via extracellular-signal-regulated kinase (ERK)1/2-mediated downstream regulation of p90RSK, c-Jun, and transcriptional changes of TRIM15 and STOM. IL-22 also promoted expression of ERK1/2-independent genes such as DDR2, LCN2, and LRG1, which are known to be involved in cell proliferation and migration. This study suggests that IL-22 induces cell proliferation in highly proliferative cells such as intestinal epithelial cells.


Assuntos
Proliferação de Células , Neoplasias do Colo/metabolismo , Enterócitos/metabolismo , Interleucinas/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Linhagem Celular Tumoral , Células Cultivadas , Neoplasias do Colo/patologia , Enterócitos/fisiologia , Humanos , Interleucinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo
20.
Int J Mol Sci ; 20(13)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262044

RESUMO

Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1ß and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.


Assuntos
Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Cognição , Hipertensão/complicações , Interleucinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Barreira Hematoencefálica/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/fisiopatologia , Permeabilidade Capilar , Córtex Cerebral/metabolismo , Fibrina/metabolismo , Hipocampo/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR
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