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One case involved a 61-year-old woman who was admitted to hospital with liver occupation, subsequently found multiple organ occupation, and was eventually pathologically identified as having immunoglobulin G4-related disease.
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In this report we highlight a case of HPS secondary to B-cell lymphoma, aiming to facilitate the early recognition and treatment of HPS in its classic presentation by clinicians.
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Ulcerative Colitis (UC) is a major type of chronic inflammatory bowel disease of the colonic mucosa and exhibits progressive morbidity. The incidence and prevalence of UC is increasing worldwide. The global burden of UC, which can substantially reduce quality of life, is clearly increasing. These data highlight the need for research into prevention of UC and innovations in health-care systems to manage this complex and costly disease. Glucagon-like peptide-1 (GLP-1), a new antidiabetic drug, is used to treat Type 2 Diabetes Mellitus (T2DM). Accumulating evidence suggests that GLP-1 has additional roles other than glucose-lowering effects. Despite the abundance of GLP-1 research, studies in UC have been less consistent, especially body weight; for example, body weight, colon length, colon injury score, intestinal microbiota, remain to be studied further. To date, the molecular mechanism of the protective effect of GLP-1 on UC remains obscure. The effect of GLP-1 was studied by using a dextran sulfate sodium (DSS)-induced colitic mice and lipopolysaccharide (LPS) treated RAW264.7 cells (macrophage cell line) under in vivo and in vitro conditions, respectively. Our results indicate that GLP-1 significantly relieves ulcerative colitis as it represses the production of proinflammatory mediators. In addition, GLP-1 blocks the activation of the protein kinase B (AKT)/nuclear factor-κB (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways. GLP-1 also alleviates DSS-induced injury to the intestinal mucosa and dysbiosis of gut microbiota. Altogether, GLP-1 has protection effect on ulcerative colitis. Thus, GLP-1 can be considered as a potential therapeutic candidate for the treatment of UC.
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Colitis Ulcerosa , Diabetes Mellitus Tipo 2 , Animales , Ratones , Calidad de Vida , Peso Corporal , Péptido 1 Similar al GlucagónRESUMEN
INTRODUCTION: Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized as a severe condition with rapid progression, poor therapeutic response and poor prognosis. Early and timely evaluation of the prognosis is helpful for providing appropriate clinical intervention and prolonging patient survival. AREAS COVERED: Currently, there are no specific dynamic and comprehensive approaches to assess the prognosis of patients with ACLF. This article reviews the progress in evaluating the short-term prognosis of ACLF to provide future directions for more dynamic prospective large-scale multicenter studies and a basis for individualized and precise treatment for ACLF patients. We searched PubMed and Web of Science with the term 'acute on chronic liver failure' and 'prognosis.' There was no date or language restriction, and our final search was on 26 October 2022. EXPERT OPINION: ACLF is a dynamic process, and the best prognostic marker is the clinical evolution of organ failure over time. New prognostic markers are developing not only in the fields of genetics and histology but also toward diversification combined with imaging. Determining which patients will benefit from continued advanced life support is a formidable challenge, and accurate short-term prognostic assessments of ACLF are a good approach to addressing this issue.
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Insuficiencia Hepática Crónica Agudizada , Trasplante de Hígado , Humanos , Insuficiencia Hepática Crónica Agudizada/diagnóstico , Insuficiencia Hepática Crónica Agudizada/terapia , Estudios Prospectivos , Pronóstico , PredicciónRESUMEN
The phenotype shift in regulatory T cells (Tregs) contributes to immunopathogenesis of autoimmune diseases. The current study was aimed to investigate the regulatory function of interleukin-35 (IL-35) to T helper 22 (Th22) cell phenotype shift in Tregs in primary biliary cholangitis (PBC). Fifty-five PBC patients and twenty-four controls were enrolled. CD4+CD25+CD127dim/- Tregs and Th22 cells were investigated by flow cytometry. Forkhead box P3 (FoxP3) and aryl hydrocarbon receptor (AhR) mRNA levels were assessed by real-time polymerase chain reaction. Plasma IL-10 and IL-22 levels were measured by ELISA. Purified Tregs were stimulated with exogenous IL-35, and were co-cultured with autologous CD4+CD25- T cells. Cellular proliferation and cytokine production was measured. Purified Tregs were also cultured into Th22 condition in the presence or absence of exogenous IL-35, and Th22 phenotype were assessed. PBC patients had lower levels of Treg percentage, FoxP3 mRNA, and plasma IL-10, while had higher levels of Th22 proportion, AhR mRNA, and plasma IL-22. Tregs from PBC patients showed reduced immunosuppressive activity, which presented as increased cellular proliferation, interferon-γ production and decreased IL-35/IL-10 secretion in co-culture system. Tregs shifted into Th22 phenotype in PBC patients with elevated CCR4, CCR6, and CCR10 expression as well as increased IL-22 production. IL-35 not only enhanced inhibitory function of Tregs but also suppressed phenotype shift of Tregs into Th22 phenotype in PBC patients. This process was accompanied by elevation of IL-10 and transforming growth factor-ß1 secretion by Tregs from PBC patients. The present data suggested that reduced IL-35 might be insufficient to maintain Tregs function and phenotype shift from Tregs into Th22 phenotype in PBC patients.
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Interleukin 35 (IL-35) mediates immunosuppression of T cells in autoimmune diseases. T cells play an important role in primary biliary cholangitis (PBC) with incompletely elucidated pathogenesis. Thus, we aimed to investigate the role of IL-35 regulation on T cells in PBC patients. Fifty-one PBC patients and 28 controls were enrolled in this study. Plasma IL-35 level was measured. Purified peripheral CD4+ and CD8+ T cells were stimulated with exogenous IL-35 to investigate their functional phenotypes. IL-35-treated CD8+ T cells were cultured with human intrahepatic biliary epithelial cell line to determine the cytotoxicity of CD8+ T cells from PBC patients. Plasma IL-35 concentration was lower in PBC patients and negatively correlated with alkaline phosphatase. CD4+ T cells from PBC patients exhibited elevated transcription factor expressions and cytokine secretion, whereas CD8+ T cells produced increased cytotoxic molecules and cytokines. In vitro IL-35 stimulation suppressed the production of IL-17 and IL-22 by CD4+ T cells from PBC patients. CD8+ T cells treated with IL-35 mediated reduced target cell death in the direct contact co-culture system in PBC patients. This process was accompanied by reduced production of cytotoxic molecules and cytokines and increased expressions of immune checkpoint receptors in CD8+ T cells. Reduced circulating IL-35 might be insufficient to suppress T cell function, leading to the immune dysregulation in PBC patients.
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Sistema Biliar , Cirrosis Hepática Biliar , Humanos , Sistema Biliar/metabolismo , Citocinas/metabolismo , Linfocitos T CD8-positivos , Linfocitos T CD4-Positivos/metabolismoRESUMEN
Interleukin (IL) -35 induces immunotolerance by suppression of CD8+ T cells during chronic infections and cancers. In the present study, we amined to investigate the role of IL-35-mediated regulation of CD8+ T cells in patients with liver cirrhosis. Seventy-one patients with liver cirrhosis (46 patients with untainted ascites and 25 patients with spontaneous bacterial peritonitis [SBP]) and 22 controls were enrolled. Plasma and ascitic IL-35 levels were measured using ELISA. Peripheral and ascitic CD4+ and CD8+ T cells were purified to investigate their functional phenotypes. IL-35-stimulated CD8+ T cells were cultured with HepG2 cells in direct and indirect contact systems. Lactate dehydrogenase expression and cytokine secretion were measured to determine the cytotoxicity of CD8+ T cells. Plasma IL-35 was elevated in patients with liver cirrhosis, and ascitic IL-35 levels were higher in the SBP group than in the untainted ascites group. No significant differences in transcription factor expression or cytokine production in peripheral and ascitic CD4+ T cells were observed among groups. In the SBP group, ascitic CD8+ T cells expressed decreased cytotoxic molecules, along with the reduced secretion of interferon-γ and tumor necrosis factor-α when compared with the untainted ascites group. IL-35 stimulation suppressed ascitic CD8+ T cell cytotoxicity and cytokine production in both direct and indirect contact culture systems. This process was accompanied by decreased cytotoxic molecule expression and increased immune-checkpoint molecules in ascitic CD8+ T cells. The present findings revealed that overexpression of ascitic IL-35 dampened the cytotoxicity of CD8+ T cells in liver cirrhotic patients with SBP.
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Ascitis , Interleucinas , Peritonitis , Ascitis/complicaciones , Líquido Ascítico/metabolismo , Linfocitos T CD8-positivos/metabolismo , Humanos , Interleucinas/metabolismo , Cirrosis Hepática/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Pradefovir is a liver-targeted prodrug of adefovir, a nucleoside/nucleotide analogue with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30, 45, 60, or 75 mg) versus tenofovir disoproxil fumarate (TDF; 300 mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study. METHODS: Treatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible. RESULTS: A total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were hepatitis B e antigen (HBeAg) positive, and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/mL, with pradefovir doses of 30-, 45-, 60-, and 75-mg, respectively, compared with 5.12 log10 IU/mL with TDF. However, HBeAg loss was attained by more participants who received 45-, 60-, or 75-mg pradefovir than by those receiving TDF (12%, 6%, and 9% vs 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30- and 45-mg groups, and serum phosphate levels were comparable among all groups. Most adverse events (AEs) were mild (grade 1). No treatment-related severe AEs were reported. Overall, AEs and laboratory abnormalities were comparable to those in the TDF group. CONCLUSIONS: Pradefovir and TDF exhibited comparable reductions in HBV DNA levels. All treatments were safe and well tolerated. CLINICAL TRIALS REGISTRATION: NCT00230503 and China Drug Trials CTR2018042.
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Hepatitis B Crónica , Profármacos , Adenina/análogos & derivados , Antivirales/efectos adversos , ADN Viral , Antígenos e de la Hepatitis B , Virus de la Hepatitis B/genética , Humanos , Compuestos Organofosforados , Profármacos/efectos adversos , Tenofovir/efectos adversos , Resultado del Tratamiento , Carga ViralRESUMEN
Natural killer-like B (NKB) cells are newly identified lymphocyte subset, which present immunomodulatory property in infectious diseases through secretion of interleukin-18 (IL-18). However, the role of NKB cells function and its regulation in hepatocellular carcinoma (HCC) is not elucidated. Seventy-two HCC patients and twenty-five controls were enrolled. Peripheral and liver-infiltrating CD3-CD19+CD56+NKp46+ cells were investigated by flow cytometry. Serum IL-35 and NKB cell-secreting cytokine level was measured by ELISA. The regulatory activity of IL-35 to peripheral and liver-infiltrating NKB cells was assessed in direct co-culture system between CD8+ T cells and HepG2 cells. Peripheral NKB cells and IL-18 secretion were reduced in HCC patients, while liver-infiltrating NKB cells and IL-18 secretion were also decreased in HCC tumor sites. Increased IL-35 level was negatively correlated with NKB cell percentage and IL-18 production in HCC. NKB cells induced the elevation of CD8+ T cell cytotoxicty, and this enhancement could be inhibited by IL-18 binding protein. IL-35 stimulation dampened NKB cell percentage and IL-18 production, leading to the suppression of NKB cell-mediated CD8+ T cell cytotoxicity in HCC patients. Our current data revealed that IL-35 might suppress NKB cell activity in HCC patients.
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Linfocitos B/efectos de los fármacos , Carcinoma Hepatocelular/inmunología , Interleucinas/farmacología , Células Asesinas Naturales/efectos de los fármacos , Neoplasias Hepáticas/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Adulto , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma Hepatocelular/metabolismo , Estudios de Casos y Controles , Técnicas de Cocultivo , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Células Hep G2 , Humanos , Interleucina-18/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Neoplasias Hepáticas/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Microambiente TumoralRESUMEN
Chronic hepatitis B virus (HBV) infection induces dysfunction of immune response and chronic liver damage. However, the mechanisms that account for HBV-related hepatocellular carcinoma (HCC) are poorly understood. The aim of present study was to investigate the modulatory role of interleukin (IL)-35, an immunosuppressive cytokine, to IL-9-secreting T cells in hepatitis B-related HCC. Twenty-two HBV-related HCC patients, twenty-seven chronic hepatitis B (CHB) patients, and eleven controls were enrolled. Serum IL-35 and IL-9 concentration was measured by ELISA. Peripheral and liver-infiltrating non-specific and HBV-specific Th9 and Tc9 cells were assessed by flow cytometry. The regulatory activity of IL-35 to peripheral and liver-infiltrating Th9 cells was assessed in co-culture system between CD8+ T cells and HepG2.2.15 cells. Serum IL-35 was up-regulated, while IL-9 was down-regulated in HBV-related HCC patients compared with in CHB patients and controls. Peripheral non-specific and HBV-specific Th9 cells, but not Tc9 cells, were decreased in HBV-related HCC patients. Liver-infiltrating non-specific and HBV-specific Th9 cells were also reduced in HCC tumor sites. CD8+ T cells from CHB and HBV-related HCC patients revealed decreased cytotoxicity compared with those from controls. Autologous Th9 cells mediated the elevation of CD8+ T cell cytotoxicity, and this process was depending on IL-9 secretion. Recombinant IL-35 stimulation inhibited IL-9 secretion and PU.1 mRNA expression in non-specific and HBV-specific Th9 cells, leading to the suppression of Th9-mediated CD8+ T cell cytotoxicity in CHB and HBV-related HCC patients. Our current data indicated that IL-35 might dampen non-specific and HBV-specific Th9 cells activity in HBV-related HCC patients.
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Linfocitos T CD4-Positivos/inmunología , Carcinoma Hepatocelular/inmunología , Hepatitis B Crónica/complicaciones , Interleucina-9/biosíntesis , Interleucinas/fisiología , Neoplasias Hepáticas/inmunología , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica , Femenino , Humanos , Interleucina-9/sangre , Interleucinas/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: In some previous studies, serum hepatitis B virus RNA (HBV RNA) was proposed as an HBV viral marker during therapy. However, the dynamic change of HBV RNA, the correlation of HBV RNA with cccDNA, and the combination of HBV RNA with known HBV markers in predicting entecavir (ETV) treatment outcome in the same cohort are rarely reported. METHODS: A total of 111 HBeAg-positive patients were enrolled in our study. The dynamic changes of serum HBV RNA and the correlation of HBV RNA with other HBV markers were investigated in the early treatment period of 144-week ETV treatment. Intrahepatic cccDNA was detected at baseline and week 48. Receiver operating characteristic analyses were used to identify HBV RNA levels associated with HBeAg seroconversion. RESULTS: The serum HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. The levels of HBV RNA decreased slower compared with the serum HBV DNA, irrespective of whether the patients achieved HBeAg seroconversion or not. Although the serum HBV RNA was positively correlated with cccDNA at baseline among all patients, no significant correlation was observed in the patients with HBeAg seroconversion at week 48 (r=0.094, P=0.588). The area under the receiver operating characteristic (AUROC) of HBV RNA and HBeAg at week 24 was 0.754 and 0.800, respectively. The AUROC of the HBV RNA and HBeAg combination had a higher value (AUROC=0.821). CONCLUSIONS: The level of HBV RNA at week 24 was a powerful predictor of HBeAg seroconversion in HBeAg-positive patients after 144-week ETV treatment, while the combination of HBV RNA and HBeAg was superior to HBV RNA alone in predicting HBeAg seroconversion.
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Antivirales/uso terapéutico , Guanina/análogos & derivados , Antígenos e de la Hepatitis B/sangre , Hepatitis B/diagnóstico , Hepatitis B/tratamiento farmacológico , ARN Viral/sangre , Seroconversión , Adulto , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Guanina/uso terapéutico , Hepatitis B/sangre , Virus de la Hepatitis B/genética , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Interleukin (IL)-35 is a newly indentified cytokine and induces immunotolerance via suppression of CD8+ T cell activity in chronic viral hepatitis. AIMS: To investigate the modulatory function of IL-35 to CD8+ T cells in viral hepatitis-induced acute-on-chronic liver failure (ACLF). METHODS: Fifty-five ACLF patients and 21 healthy controls were enrolled. Serum IL-35 concentration was measured by ELISA. Absolute accounts for T cells, immune checkpoint molecules, and cytotoxic molecules in CD8+ T cells were measured by flow cytometry and real-time PCR, respectively. Direct and indirect contact co-culture systems between CD8+ T cells and HepG2 cells were set up. The regulatory function of IL-35 to CD8+ T cells was assessed by measuring lactate dehydrogenase expression and cytokine production. RESULTS: Serum IL-35 concentration was elevated in ACLF patients and positively correlated with total bilirubin, but negatively correlated with prothrombin time activity. Peripheral CD8+ T cells showed exhausted phenotype in ACLF patients, which manifested as up-regulation of programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) but down-regulation of perforin, granzyme B, and FasL. Recombinant IL-35 stimulation dampened cytotoxicity and interferon-γ production in both direct and indirect contact co-culture systems. This process was accompanied by elevation of PD-1, CTLA-4, and LAG3, as well as reduction of perforin, granzyme B, and FasL in CD8+ T cells. CONCLUSION: Elevated IL-35 suppressed both cytolytic and non-cytolytic activity of CD8+ T cells in ACLF patients.
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Insuficiencia Hepática Crónica Agudizada , Linfocitos T CD8-positivos/inmunología , Hepatitis Viral Humana , Tolerancia Inmunológica , Interleucinas , Activación de Linfocitos/inmunología , Insuficiencia Hepática Crónica Agudizada/sangre , Insuficiencia Hepática Crónica Agudizada/inmunología , Bilirrubina/sangre , Técnicas de Cocultivo/métodos , Pruebas Inmunológicas de Citotoxicidad/métodos , Femenino , Células Hep G2 , Hepatitis Viral Humana/sangre , Hepatitis Viral Humana/inmunología , Humanos , Interleucinas/sangre , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Tiempo de Protrombina/métodos , Proteínas Recombinantes/sangre , Proteínas Recombinantes/inmunologíaRESUMEN
Interleukin (IL)-35 is a newly identified IL-12 cytokine family member, which has been demonstrated to induce immunotolerance by suppression of CD8+ T cells function in chronic viral hepatitis. However, the role of IL-35 in modulating CD8+ T cells activity in non-viral hepatitis-related hepatocellular carcinoma (HCC) was not fully elucidated. Forty-four patients with non-viral hepatitis-related HCC and 20 healthy individuals were enrolled. Serum IL-35 concentration was measured by ELISA. CD8+ T cells were purified from peripheral bloods and liver tissues. mRNA expression of cytotoxic/inhibitory molecules in CD8+ T cells with IL-35 stimulation was semi-quantified by real-time PCR. Direct and indirect contact co-culture systems of CD8+ T cells and HCC cell lines were set up. The modulatory function of IL-35 on peripheral and liver-resident CD8+ T cells was assessed by measurement of lactate dehydrogenase release and cytokine production in the co-culture supernatants. Serum IL-35 was notably elevated in HCC patients, while effective anti-tumor therapies down-regulated IL-35 concentration. Recombinant IL-35 stimulation suppressed cytotoxicity and proinflammatory cytokine secretion of peripheral and liver-resident CD8+ T cells in direct and indirect contact co-culture systems. This process was accompanied by reduction of perforin expression and interferon-γ production, as well as programmed death-1 and cytotoxic T-lymphocyte-associated protein 4 elevation in CD8+ T cells. The current data suggested that IL-35 inhibited both cytolytic and non-cytolytic function of CD8+ T cells to non-viral hepatitis-related HCC probably via repression of perforin expression. IL-35 might be considered to be one of the therapeutic targets for patients with HCC.
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Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Hepatitis/inmunología , Interleucinas/inmunología , Neoplasias Hepáticas/inmunología , Adulto , Linfocitos T CD8-positivos/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Células Cultivadas , Técnicas de Cocultivo , Citocinas/inmunología , Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/inmunología , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Células Hep G2 , Hepatitis/metabolismo , Humanos , Interleucinas/genética , Interleucinas/farmacología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Perforina/genética , Perforina/inmunología , Perforina/metabolismo , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacologíaRESUMEN
BACKGROUND: Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. METHODS: A total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/- Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA. RESULTS: Peripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro. CONCLUSION: Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection.
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Hepatitis B Crónica/inmunología , Interleucinas/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Adolescente , Adulto , ADN Viral/genética , Femenino , Virus de la Hepatitis B/inmunología , Humanos , Inmunosupresores , Interleucina-10/genética , Masculino , Adulto JovenRESUMEN
BACKGROUND: Hepatic fibrosis is a reversible pathological process. Inflammatory responses are the prevailing reactions during hepatic fibrosis. Decoy receptor 3 (DcR3) has been reported to have an anti-inflammatory effect. OBJECTIVES: The aim of the study was to investigate the preventive effects of DcR3 on hepatic fibrosis. MATERIAL AND METHODS: Hepatic fibrosis was induced in rats by administering intraperitoneally (ip.) 1% dimethylnitrosamine (DMN). DcR3 plasmid was delivered into rats by intravenous injection. After 4 weeks, the expression of DcR3, TNF-like molecule 1A (TL1A) and α-SMA of the liver tissue were checked. The levels of inflammatory cytokines such as TNF-α, IL-6 and IL-1ß were detected using western blotting and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Masson's trichrome staining for histopathological changes of the liver tissue was observed. Finally, the activity of NF-κB in the liver was examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: A higher expression of DcR3 was observed in rats treated with DcR3 (p < 0.05). Histological results showed that DcR3 significantly attenuated pathology in hepatic fibrosis rats. Consistently, mRNA and protein levels of α-SMA, TL1A, TNF-α, IL-6, and IL-1ß were repressed in the liver tissue after treatment with DcR3 (p < 0.05). Moreover, DcR3 also inhibited the activation of NF-κB in the liver tissue (p < 0.05). CONCLUSIONS: This study demonstrated that DcR3 attenuated liver injury and inflammatory responses in rats with hepatic fibrosis. We suggest DcR3 may be a prophylactic and promising therapeutic agent in the treatment of hepatic fibrosis.
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Inflamación/prevención & control , Cirrosis Hepática/prevención & control , FN-kappa B/inmunología , Miembro 6b de Receptores del Factor de Necrosis Tumoral/farmacología , Animales , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Inflamación/genética , FN-kappa B/metabolismo , Ratas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunologíaRESUMEN
The mechanisms of hepatitis B virus (HBV) persistent infection are not completely understood. Interleukin (IL)-35, which is a newly identified cytokine belongs to IL-12 family, has been demonstrated to induce immunotolerance. Thus, the aim of current study was to investigate the role of IL-35 during chronic HBV infection. A total of 61 patients with chronic HBV infection [37 chronic hepatitis B (CHB) and 24 asymptomatic HBV carriers (ASC)] and 20 healthy individuals were enrolled. IL-35 concentration as well as the modulatory function of IL-35 on CD4+CD25+CD127dim/- regulatory T cells (Tregs) and on HBV antigen-specific CD8+ T cells was investigated. IL-35 expression was significantly increased in both CHB and ASC, and was positively correlated with the levels of HBV DNA. Inhibition of viral replication induced the reduction in serum levels of IL-35. IL-35 stimulation led to inhibition of proinflammatory cytokine productions and elevation of apoptosis in peripheral blood mononuclear cells (PBMCs), but not in HepG2.2.15 cells. Moreover, IL-35 stimulation not only robustly inhibited cellular proliferation, but also up-regulated the production of IL-10 and IL-35 in a HBV antigen-specific and non-specific manner in Tregs/CD4+CD25- T cells coculture system, which indicated enhancement of suppressive function of Tregs. Furthermore, IL-35 also reduced both cytolytic activity (direct lysis of HepG2.2.15 cells) and noncytolytic function (IFN-γ and TNF-α production) of HBV antigen-specific CD8+ T cells. The current data suggested that IL-35 contributed to maintain viral persistence by suppressing antiviral immune responses and reducing inflammatory responses in chronic HBV infection.
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Antivirales/uso terapéutico , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Interleucinas/inmunología , Interleucinas/farmacología , Adolescente , Adulto , Antígenos Virales/inmunología , Apoptosis/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , ADN Viral , Femenino , Células Hep G2 , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Humanos , Tolerancia Inmunológica/inmunología , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Interleucina-12 , Interleucinas/sangre , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Replicación Viral , Adulto JovenRESUMEN
Interleukin (IL)-35, a newly identified member of the IL-12 cytokine family, has been reported to suppress inflammation and induce immunotolerance. However, little is known regarding the role of IL-35 during chronic hepatitis C virus (HCV) infection. Herein, we measured the serum IL-35 concentration of 73 patients with hepatitis C and 22 healthy individuals, as well as further investigated the modulatory function of IL-35 on CD4+CD25+CD127dim/- regulatory T cells (Tregs) and on hepatocytes infected with HCV in cell culture (HCVcc). IL-35 expression was significantly increased in patients with chronic hepatitis C and was positively correlated with the levels of HCV RNA. Inhibition of viral replication led to decreases in the serum levels of IL-35. IL-35 stimulation not only elevated the percentage of Tregs but also robustly inhibited cellular proliferation and up-regulated the production of anti-inflammatory cytokines (e.g., IL-10 and IL-35) in a HCV-specific and non-specific manner, which indicates enhancement of the suppressive function of Tregs. Although IL-35 did not exert anti-HCV activity in HCVcc-infected Huh7.5 cells, it reduced inflammatory cytokine secretion from Huh7.5 cells. This was probably via inhibition of the STAT1 and STAT3 signaling pathways, which could suppress subsequent liver damage due to chronic hepatitis C. The current data suggested that IL-35 contributes to persistent HCV infection by inhibiting antiviral immune activity. Moreover, IL-35 might also protect against HCV-induced liver injury by down-regulating the expression of proinflammatory cytokines. Thus, the immunosuppressive properties of IL-35 might play contradictory roles in maintaining viral persistence and reducing the inflammatory responses in chronic HCV infection.
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Hepacivirus/fisiología , Hepatitis C Crónica/inmunología , Hepatocitos/fisiología , Interleucinas/inmunología , Linfocitos T Reguladores/inmunología , Línea Celular Tumoral , Técnicas de Cocultivo , Hepatocitos/virología , Humanos , Tolerancia Inmunológica , Inmunidad , Interleucina-10/metabolismo , ARN Viral/genética , Receptores de Complemento 3b/metabolismo , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Linfocitos T Reguladores/virología , Latencia del Virus , Replicación ViralRESUMEN
We investigated the efficacy and safety of a new type of dietary fiber (high specific volume polysaccharide) for use in treating constipation of different etiologies. Functional constipation patients and irritable bowel syndrome-constipation (IBS-C) patients were administrated high specific volume polysaccharide (HSVP) three times daily for a period of 2 wk to relieve their symptoms. Scores on a stool form scale, and patient reports of straining during a bowel movement, having sensations of an incomplete bowel movement or a blocked anorectum, and abnormal defecation intervals were recorded, graded, and scored by a functional constipation sample group. Similarly, a cohort of IBS-C patients reported their occurrence of abdominal discomfort or pain, abnormal stool formation, defecation frequency, and straining during a bowel movement. Additionally, both groups reported any adverse reactions associated with taking HSVP. All patients in both groups returned for follow-up visits, and no adverse reactions to treatment with HSVP were reported. In the functional constipation group, HSVP was effective for treating symptoms of constipation in 81.46% and 93.17% of patients after 7 and 14 d of dosing, respectively (both p<0.05). In the IBS-C group, symptoms of constipation were relieved in 71.67% and 88.34% of patients after 7 and 14 d of dosing, respectively (both p<0.05). High specific volume polysaccharide was shown be effective for treatment of functional constipation and IBS-C, without causing significant adverse events.
Asunto(s)
Estreñimiento/tratamiento farmacológico , Defecación/efectos de los fármacos , Fibras de la Dieta/administración & dosificación , Síndrome del Colon Irritable/complicaciones , Polisacáridos/administración & dosificación , Adulto , Estreñimiento/etiología , Estreñimiento/fisiopatología , Heces , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the antitumor efficiency of IL-12 gene induced by RU486 regulatory system in a mouse model of orthotopically transplanted hepatoma. METHODS: The orthotopic hepatoma model was prepared by inoculation of H22 hepatoma cells into the mouse liver. Murine interleukin-12 (IL-12) expressing plasmid pRS22 containing RU486 regulatory system was injected into mice by a hydrodynamic injection 3 days after H22 cells inoculation. Three days after hydrodynamic injection, the mice were induced with RU486 (250 µg/kg) consecutive intraperitoneal administration for 6 days. Blood samples were taken at 10 h after the first and third induction for the determination of IL-12, IFN-γ and NO. Five mice were sacrificed at 2 days after the treatment with RU486. The tumor size was measured. HE and immunohistochemical stainings were applied to evaluate the proliferative activity and angiogenesis in the tumors. The other 7 mice were kept to monitor their survival. RESULTS: In mice receiving saline plus RU486, pRS-LacZ plus RU486, or pRS22 plus sesame oil, the liver tumors were big in size: (409.90 ± 137.03) mm(3), (271.80 ± 182.63) mm(3) and (251.00 ± 76.55) mm(3), respectively. Strong PCNA positive expression [(82.10 ± 4.62)%, (83.45 ± 2.34)% and (77.46 ± 2.99)%] and extensive microvessel density (74.58 ± 18.47, 63.60 ± 13.36 and 53.52 ± 11.74 per 400 × field), respectively, in these tumor tissues were observed after immunohistochemical staining. The survival period was shorter in these mice. In contrast, in mice treated with pRS22 plus RU486, the tumor was smaller in size. Extensive necrosis, weak PCNA proliferative activity (50.67 ± 8.09)%, and a marked paucity of microvessel density (25.38 ± 10.87) were seen. The survival of mice was obviously prolonged. Compared with the 3 control groups, a significant elevation of serum IL-12, IFN-γ and NO levels were detected in the mice treated with pRS22 plus RU486. CONCLUSION: Expression of IL-12 gene can be effectively controlled by a RU486 regulatory system. The inducible IL-12 can delay the growth of orthotopically transplanted hepatoma and prolong the survival of mice.