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1.
Mikrobiyol Bul ; 55(3): 374-388, 2021 Jul.
Artigo em Turco | MEDLINE | ID: mdl-34416803

RESUMO

Some single nucleotide polymorphisms (SNPs) of the gene encoding interleukin 28B (IL28B) may increase susceptibility to infection and chronicity in humans with hepatitis B and C viruses. In our study, we aimed to investigate the prevalence of rs12979860, rs8099917 and rs12980275 SNPs in IL28B in patients with hepatitis B (HBV) or hepatitis C Virus (HCV) infection and to determine the relationship of these polymorphisms with plasma IL28B levels. For this purpose, 64 HBV-infected and 66 HCV-infected patients and 70 healthy individuals were included in the study. The SNPs were investigated by real time PCR (Polimerase Chain Reaction, Rt-PCR) using TaqMan SNP Genotyping Assay. The plasma levels of IL28B were detected by 'Enzyme Linked Immunosorbent Assay (ELISA)'. The frequencies of the rs12980275AG genotype and G allele (p= 0.003 and p= 0.04, respectively), and the rs12979860CT genotype and T allele (p= 0.01 and p= 0.04, respectively) were lower in HBV-infected patients. In HCV-infected patients, the rs8099917TG genotype and G allele frequencies (p= 0.04) were higher and the TGG haplotype showed a statistically significant difference (p= 0.04). The mean of IL28B plasma levels were higher in the control group than the HBV or HCV-infected patient groups (p= 0.001 and p= 0.01, respectively). However, HBV-infected patients with the rs12980275AG genotype showed a significant difference in plasma IL28B levels compared to the other genotypes (p= 0.0001) and these patients had lower viral loads (<105 IU/ml). According to the results of the study, it can be stated that rs12979860CT and rs12980275AG genotypes may play a role in preventing the chronicity of HBV infection, while rs8099917TG genotype may contribute to the transformation of HCV infection into chronic infection. In this study, it was observed that the presence of the G allele for the rs8099917 polymorphism could be evaluated as a risk allele for chronic HCV infection and that the TGG haplotype could have a strong predictive effect on increasing susceptibility to chronic HCV infection. It is recommended to evaluate the genotypic distribution of IL28B before treatment because of its prognostic significance in HBV or HCV infected patients. In HBV infection, the rs12980275AG genotype which is thought to have a protective effect by limiting viral replication with increased plasma IL28B levels, can be used as a good prognostic factor. These polymorphisms could be used as biomarkers to predict the clinical consequences of the patients infected with HBV or HCV, to take precautions to prevent the chronicity of the infection and its complications, and to develop new molecular targeted therapies with further research.


Assuntos
Hepatite B Crônica , Hepatite C Crônica , Hepatite B Crônica/genética , Hepatite C Crônica/genética , Humanos , Interferons , Interleucinas/genética
2.
Nat Commun ; 12(1): 4882, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385466

RESUMO

Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment-induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and have more than a 90% probability to develop chronic hepatitis C (CHC). Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV. Here we describe an effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells are significantly weaker activators of HCV specific CD8+ T cells than unstressed cells. This is not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses are restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impairs HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4-HCV paradox.


Assuntos
Apresentação do Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Interleucinas/imunologia , Ativação Linfocitária/imunologia , Células A549 , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Linhagem Celular Tumoral , Regulação da Expressão Gênica/imunologia , Genótipo , Células Hep G2 , Hepacivirus/genética , Hepacivirus/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucinas/genética , Interleucinas/metabolismo
3.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360971

RESUMO

Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1ß. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1ß suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22.


Assuntos
Anti-Inflamatórios/farmacologia , Imunoglobulina G/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucinas/genética , Transcriptoma/efeitos dos fármacos , Biomarcadores/metabolismo , Células HT29 , Humanos , Imunoglobulina G/metabolismo , Interleucinas/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34360569

RESUMO

Hepatocellular carcinoma (HCC) is a malignancy with a leading lethality. The etiology is quite diverse, ranging from viral infections to metabolic disorders or intoxications, and associates with specific somatic mutational patterns and specific host immunological phenotypes. Particularly, hepatitis C virus (HCV)-infected liver is featured by an activation of interferon (IFN)-stimulated genes (ISGs; IFN signature), which we suppose is driven by type III IFNL4. Taking advantage of the TCGA collection of HCC patients of various different etiologies, this study aimed at validating our previous findings on hepatic IFNL4 gene activation in HCV infection in an independent and larger cohort of patients with advanced liver disease. In a cohort of n = 377 cases, the entirety of the sequencing data was used to assess the IFNL genotypes, and the cases were stratified for etiology. The number of IFNL4 transcripts within nonmalignant and malignant tissues was found to be more abundant in patients with HCV or HCV/HBV infections when compared to other risk factors. Moreover, in patients with HCV infection as a risk factor, a close, positive relationship was found between ISG activation and the number of functional IFNL4 transcripts. Data on this independent TCGA sample support the concept of an IFNL4-dependent HCV-driven activation of hepatic ISGs. In addition to that, they add to the understanding of etiology-related host immunological phenotypes in HCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Hepatite C Crônica/complicações , Interleucinas/metabolismo , Neoplasias Hepáticas/patologia , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Interleucinas/genética , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
5.
Front Cell Infect Microbiol ; 11: 656393, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307188

RESUMO

Sustained virologic response (SVR) in chronic hepatitis C (CHC) treatment denotes that the host genetics controls the immune response and unequivocally contribute to viral clearance or disease severity. In this context, single nucleotide polymorphisms (SNPs) in the locus of interferon lambda 3 and 4 genes (IFNL3/4) have been important genetic markers of responsiveness to CHC as prognostic markers for the pegylated-Interferon-alpha/ribavirin (Peg-IFN-α/RBV). Here, we analyzed 12 SNPs at the IFNL3/4 region in 740 treatment-naïve patients with CHC infected with hepatitis C virus (HCV) genotypes 1, 2, or 3 treated with Peg-IFN-α/RBV. Individually, rs12979860-CC, rs8109886-CC, or rs8099917-TT were predictive markers of SVR, while rs12979860-CC demonstrated the stronger effect. Besides, the genotypic combination of these three predictors' genotypes, CC/CC/TT, increased the rate of SVR. Serum levels of cytokines and gene expression analysis on the genes IFNL3, IFNL4, IFNA1, and some of the IFN-stimulated genes (ISGs) were measured in a subgroup of 24 treated patients and 24 healthy volunteers. An antagonist effect was highlighted between the expression of IFNL3/4 and IFNA1 mRNA among patients. Besides, a prominent production of the pro-inflammatory chemokines CCL4 and CXCL10 was observed at a 12-week treatment follow-up. Lower serum levels of these chemokines were detected in patients with an rs12979860-CC genotype associated with the better treatment outcome. Also, lower expression levels of the IFI6, IFI16, IRF9 genes were observed among rs12979860-CC individuals. In conclusion, a combination of the genotypes at the IFNL3/4 locus can act as a better marker for the prognosis for virological responses in an admixed Brazilian population presenting the modulating effect over innate immunity and inflammation that are controlling the outcome of the viral infection, but also other infectious diseases. This study is registered on the ClinicalTrials.gov platform (accession number NCT01889849 and NCT01623336).


Assuntos
Antivirais , Interleucinas , Antivirais/uso terapêutico , Brasil , Quimioterapia Combinada , Genótipo , Humanos , Imunidade Inata , Interferon-alfa/uso terapêutico , Interferons , Interleucinas/genética , Polietilenoglicóis/uso terapêutico , Polimorfismo de Nucleotídeo Único , Proteínas Recombinantes , Resposta Viral Sustentada , Resultado do Tratamento , Carga Viral
6.
Gene ; 800: 145837, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34274469

RESUMO

Diarrhoea is a widespread disease in captive rhesus macaques (Macaca mulatta) and a small proportion of individuals may experience persistent diarrhoea. Persistent diarrhoea can lead to a compromised immune system, intestinal inflammation and malnutrition. We analyzed the blood transcriptomes of 10 persistent diarrhoeal and 12 healthy rhesus macaques to investigate the gene expression differences between the two groups. We identified 330 DEGs between persistent diarrhoeal and healthy rhesus macaques. The 211 up-regulated DEGs in the diarrhoeal group were mainly enriched in immune-related and interleukin-related categories. Among them, three interleukin (IL) 18 related DEGs (IL18, IL18R1, and IL18BP) played important roles in actively regulating pro-inflammatory responses. Interestingly, the up- and down-regulated DEGs were both enriched in the same immune-related categories. Thus, we applied a new method to examine the distribution of DEGs in all child categories. We found that interleukin and T cell related categories were mainly occupied by up-regulated DEGs, while immunoglobulin production and B cell related categories were enriched by down-regulated DEGs. We also compared rhesus macaque DEGs with the DEGs of inflammatory bowel disease (IBD) humans and IBD mouse models and found that 30-40% of macaque DEGs were shared with IBD humans and mouse models. In conclusion, our results showed that there were significant immune differences between persistent diarrhoeal rhesus macaques and healthy macaques, which was similar to the expression differences in IBD patients and mouse models.


Assuntos
Diarreia/veterinária , Doenças Inflamatórias Intestinais/genética , Doenças dos Macacos/genética , Animais , Estudos de Casos e Controles , Diarreia/genética , Diarreia/imunologia , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/etiologia , Interleucinas/genética , Macaca mulatta , Masculino , Camundongos , Doenças dos Macacos/imunologia
7.
J Med Virol ; 93(10): 5853-5863, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34081354

RESUMO

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) infection may rely on a potential genetic background for the variations in the inflammatory response. We aimed to investigate the possible correlation between polymorphisms in the IL-6 gene at rs1800796/rs1800795, in IL-6R at rs2228145, in IL-10 at rs1800896 and rs1800871, in IL-17 at rs2275913 and rs763780 loci, and COVID-19 prevalence and mortality rates among populations of 23 countries. METHODS: We searched the literature for polymorphisms in China, Japan, India, Spain, Mexico, Sweden, Turkey, Brazil, Russia, Poland, Italy, South Africa, Netherlands, Greece, Germany, UK, Iran, Finland, Czechia, Tunisia, Norway, Egypt, Croatia. We recorded the prevalence and mortality rates (per million) caused by the Coronavirus infection recorded on 7th September 2020 and 6th December 2020. RESULTS: There was a significant positive correlation between the frequency of AG genotype of rs1800896 and prevalence recorded on 6th December 2020 (r: 0.53, r2 : 0.28, p < .05). There was a significant negative correlation between the mortality rates recorded on 7th September, and the AG genotype of rs2275913 (r: -0.51, r2 : 0.26, p < .05). There was a significant positive correlation between the prevalence recorded on 6th December, and TT genotype at rs763780 (r: 0.65, r2 :0.42, p < .05) while a negative correlation between prevalence and TC genotype at rs763780 (r: -0.66, r2 : 0.43, p < .05). Also, a significant negative correlation was found between mortality rates recorded on 6th December 2020 and CC genotype at rs763780 (r: -0.56, r2 : 0.31, p < .05). CONCLUSION: The variations in prevalence of COVID-19 and its mortality rates among countries may be explained by the polymorphisms at rs1800896 in IL-10, rs2275913 in IL-17A, and rs763780 loci in the IL-17F gene.


Assuntos
COVID-19/epidemiologia , COVID-19/genética , Interleucinas/genética , COVID-19/mortalidade , Estudos de Associação Genética , Genótipo , Humanos , Interleucina-10/genética , Interleucina-17/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Prevalência , Receptores de Interleucina-6/genética , SARS-CoV-2
8.
J Biol Regul Homeost Agents ; 35(3): 987-999, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34159768

RESUMO

Chronic obstructive pulmonary disease (COPD) represents a chronic inflammatory disorder of the airways induced mainly by cigarette smoking. In the current study, cigarette smoke extract (CSE) was used to develop an in vitro COPD model using human bronchial epithelium (HBE) cells to expound the possible role of microRNA-29b (miR-29b) in COPD. Firstly, miR-29b and interleukin (IL)-22 expression was assessed in serum of 20 healthy non-smokers, 20 healthy smokers and 20 COPD patients as well as CSE-treated HBE cells. Then, miR-29b and IL-22 expression was altered to evaluate their functions in Th17/Treg ratio. miR-29b inhibited Th17/Treg ratio and levels of IL-22; whereas overexpression of IL-22 reversed these trends. Moreover, rescue experiments found that IL-22 neutralized the repressive effects of miR-29b on Th17/Treg ratio and inflammatory response. Finally, we found that miR-29b blocked the JAK/STAT3 pathway in CSE-treated HBE cells. These data highlighted that miR-29bs modulated Th17/Treg imbalance in CSE-induced experimental COPD through inhibition of IL-22-dependent JAK/STAT3 pathway.


Assuntos
MicroRNAs , Doença Pulmonar Obstrutiva Crônica , Humanos , Interleucinas/genética , MicroRNAs/genética , Doença Pulmonar Obstrutiva Crônica/genética , Linfócitos T Reguladores
10.
Scand J Gastroenterol ; 56(7): 849-854, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34078234

RESUMO

OBJECTIVES: Despite recombinant interferon-λ 4 (IFN-λ4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-λ4 may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). MATERIALS AND METHODS: Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. RESULTS: Patients producing IFN-λ4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-λ4 (IFNL4rs12979860 CT/TT versus CC, p<.0001, Mann-Whitney U-test). Additionally, in univariate analyses S/CO was significantly higher in men than women (p<.001), as well as in patients with absent/mild interface hepatitis (Ishak grade 0-2 versus 3-4, p = .009), and absent/mild steatosis (grade 0-1 versus 2-3, p = .0005). Also, an inverse correlation with HCV RNA level (rs= -0.14, p = .02) was noted. In multivariate analysis IFN-λ4, gender, steatosis and viral load remained independently associated. CONCLUSIONS: To our knowledge, this is the first report that demonstrates that the ability to produce IFN-λ4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-λ4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection. ClinicalTrials.gov Identifier: NCT00143000.


Assuntos
Hepatite C Crônica , Hepatite C , Animais , Antivirais/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferons/uso terapêutico , Interleucinas/genética , Masculino , Polimorfismo de Nucleotídeo Único , Carga Viral
11.
Theranostics ; 11(15): 7308-7321, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34158852

RESUMO

Dendritic cells (DCs) can process the antigens of cancer vaccine and thus stimulate the CD8+ T cells to recognize and kill the tumor cells that express these antigens. However, lack of promising carriers for presenting the antigens to DCs is one of the main barriers to the development of clinically effective cancer vaccines. Another limitation is the risk of inflammatory side effects induced by the adjuvants. It is still unclear how we can develop ideal adjuvant-free DC vaccine carriers without adjuvants. Methods: A 12-mer peptide carrier (CBP-12) with high affinity for Clec9a expressed on DCs was developed using an in silico rational optimization method. The therapeutic effects of the adjuvant-free vaccine comprising CBP-12 and exogenous or endogenous antigenic peptides were investigated in terms of antigen cross-presentation efficacy, specific cytotoxic T lymphocyte response, and antitumor activity. We also explored the mechanism involved in the antitumor effects of the adjuvant-free CBP-12 vaccine. Finally, we assessed the effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Results: Here, we developed CBP-12 as a vaccine carrier that enhanced the uptake and cross-presentation of the antigens, thus inducing strong CD8+ T cell responses and antitumor effects in both anti-PD-1-responsive (B16-OVA) and -resistant (B16) models, even in adjuvant-free conditions. CBP-12 bound to and activated Clec9a, thereby stimulating Clec9a+ DC to product IL-21, but not IL-12 by activating of Syk. The antitumor effects of the CBP-12 conjugated peptide vaccines could be blocked by an IL-21 neutralizing antibody. We also observed the synergistic antitumor effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Conclusions: CBP-12 could serve as an adjuvant-free peptide vaccine carrier for cancer immunotherapy.


Assuntos
Vacinas Anticâncer , Células Dendríticas/imunologia , Sistemas de Liberação de Medicamentos , Interleucinas/imunologia , Lectinas Tipo C/imunologia , Melanoma Experimental/imunologia , Peptídeos , Receptores Imunológicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Quinase Syk/imunologia , Animais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/farmacologia , Feminino , Interleucinas/genética , Lectinas Tipo C/genética , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Knockout , Peptídeos/imunologia , Peptídeos/farmacologia , Receptores Imunológicos/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Quinase Syk/genética , Vacinas de Subunidades/imunologia , Vacinas de Subunidades/farmacologia
12.
Exp Parasitol ; 226-227: 108122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34115995

RESUMO

Visceral leishmaniasis (VL) is an infectious disease caused by an intracellular protozoan belonging to Leishmania species. Interleukin (IL)-22 plays an important role in inflammatory response, chemotaxis, regulation of cellular proliferation and tissue repair. Considering the role of IL-22 in control of leishmaniasis and the effect of its single nucleotide polymorphisms (SNPs) on respective function and production, this study aimed to investigate the probable association of IL-22 SNPs with VL. The study was carried out on 110 patients with VL, 102 healthy individuals with negative leishmanin skin test (negative control group (NCG)), and 144 healthy individuals with positive leishmanin skin test (LSTPG). Four SNPs in IL-22 including rs2227501, rs2227503, rs2227513 and rs1026786 were analyzed by polymerase chain reaction-restricted fragment length polymorphism (PCR- RFLP) in the study groups. The frequency of A allele and AA genotype at rs1026786 were significantly higher in the LSTPG group than in the patients (P = 0.013 and P = 0.001, respectively). Conversely, the frequency of AG genotype was significantly higher in the patients and the NCG than in the LSTPG group (P = 0.0001 and P = 0.002, respectively). For rs2227503, the frequency of AG genotype was significantly higher in the LSTPG group than in the NCG (P = 0.025). The haplotype TGAA frequency was significantly higher in the NCG, compared to patients and LSTPG group (P = 0.004 and P = 0.023, respectively). The frequencies of haplotypes TAAG and TGAG were significantly higher in the patients than in the LSTPG group (P = 0.046 and P = 0.014, respectively). The TAAA/TAAG frequency was significantly higher in the patients than in the LSTPG group (P = 0.013). Inheritance of rs1026786 A allele and AA genotype of IL-22 could be a possible protective factor against VL, whereas the inheritance of the haplotypes TAAG and TGAG may predispose Iranian population to the disease.


Assuntos
Predisposição Genética para Doença , Interleucinas/genética , Leishmaniose Visceral/imunologia , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
13.
Mol Cells ; 44(6): 384-391, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34098591

RESUMO

The recent appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people around the world and caused a global pandemic of coronavirus disease 2019 (COVID-19). It has been suggested that uncontrolled, exaggerated inflammation contributes to the adverse outcomes of COVID-19. In this review, we summarize our current understanding of the innate immune response elicited by SARS-CoV-2 infection and the hyperinflammation that contributes to disease severity and death. We also discuss the immunological determinants behind COVID-19 severity and propose a rationale for the underlying mechanisms.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Interações Hospedeiro-Patógeno/imunologia , SARS-CoV-2/patogenicidade , Síndrome Respiratória Aguda Grave/imunologia , Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , COVID-19/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Dexametasona/uso terapêutico , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interleucinas/genética , Interleucinas/imunologia , SARS-CoV-2/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Transdução de Sinais , Análise de Sobrevida
14.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069352

RESUMO

Ulcerative colitis (UC), a severe chronic disease with unclear etiology that is associated with increased risk for colorectal cancer, is accompanied by dysregulation of cytokines. Epstein-Barr virus-induced gene 3 (EBI3) encodes a subunit in the unique heterodimeric IL-12 cytokine family of either pro- or anti-inflammatory function. After having recently demonstrated that upregulation of EBI3 by histone acetylation alleviates disease symptoms in a dextran sulfate sodium (DSS)-treated mouse model of chronic colitis, we now aimed to examine a possible further epigenetic regulation of EBI3 by DNA methylation under inflammatory conditions. Treatment with the DNA methyltransferase inhibitor (DNMTi) decitabine (DAC) and TNFα led to synergistic upregulation of EBI3 in human colon epithelial cells (HCEC). Use of different signaling pathway inhibitors indicated NFκB signaling was necessary and proportional to the synergistic EBI3 induction. MALDI-TOF/MS and HPLC-ESI-MS/MS analysis of DAC/TNFα-treated HCEC identified IL-12p35 as the most probable binding partner to form a functional protein. EBI3/IL-12p35 heterodimers (IL-35) induce their own gene upregulation, something that was indeed observed in HCEC cultured with media from previously DAC/TNFα-treated HCEC. These results suggest that under inflammatory and demethylating conditions the upregulation of EBI3 results in the formation of anti-inflammatory IL-35, which might be considered as a therapeutic target in colitis.


Assuntos
Colite Ulcerativa/genética , Interleucinas/genética , Interleucinas/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Linhagem Celular , Colite/genética , Colo/patologia , Metilação de DNA/genética , Epigênese Genética/genética , Expressão Gênica/genética , Humanos , Interleucina-12/metabolismo , Mucosa Intestinal/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/genética , Espectrometria de Massas em Tandem/métodos , Fator de Necrose Tumoral alfa/metabolismo
15.
Acta Virol ; 65(2): 141-148, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34130465

RESUMO

Direct acting antiviral agents (DAAs) are a group of antiviral drugs that inhibit specific non-structural proteins of the virus and disrupt viral replication and infection. DAAs regimens for hepatitis C virus (HCV) infection provide a particular event to tackle mechanistic intracellular relationships between the innate immunity and HCV, potentially providing perceptions about the rate of the viral replication and complex decay. Interleukin 29 (IL-29) prevents the replication of HCV. IFN-inducible protein 10 (IP-10) plays a significant role in the pathogenesis of HCV infection. MIG/CXCL9 are produced by inflammatory and stromal cells such as hepatocytes following either stimulation by interferon lambda (IFNγ) or viral infection. This study aimed to evaluate the co-expression of IL-29, IP-10 and MIG in peripheral blood mononuclear cells (PBMCs) from untreated and treated chronic HCV patients with DAAs. This study included group of twenty naïve HCV patients, group of twenty sustained viral response (SVR) patients and a control group that consisted of 10 healthy subjects. All subjects were tested for liver enzymes, serum albumin level, total serum bilirubin, platelet count, prothrombin activity and viral load. Relative gene expression of IL-29, IP-10, and MIG in PBMCs from all subjects was determined using real time PCR. The mean value of IL-29, IP-10 and MIG gene expression significantly increased in both naïve HCV and SVR groups of patients as compared to normal subjects. The corresponding value was significantly lower in patients with SVR compared to naïve HCV patients. Infection with HCV significantly trigged the co-expression of IL-29, IP-10, and CXCL9 (MIG) genes in PBMCs of chronic hepatitis C patients and significantly down-regulated in those who achieved SVR after successful DAAs therapy. Keywords: IP10; MIG; IL29; HCV; DAAs; gene expression.


Assuntos
Hepatite C Crônica , Antivirais/uso terapêutico , Quimiocina CXCL10/genética , Egito , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Humanos , Interleucinas/genética , Leucócitos Mononucleares , Monocinas/uso terapêutico
16.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074061

RESUMO

BACKGROUND: Erythritol, a sugar alcohol, is widely used as a substitute for sugar in diets for patients with diabetes or obesity. METHODS: In this study, we aimed to investigate the effects of erythritol on metabolic disorders induced by a high-fat diet in C57BL/6J mice, while focusing on changes in innate immunity. RESULTS: Mice that were fed a high-fat diet and administered water containing 5% erythritol (Ery group) had markedly lower body weight, improved glucose tolerance, and markedly higher energy expenditure than the control mice (Ctrl group) (n = 6). Furthermore, compared with the Ctrl group, the Ery group had lesser fat deposition in the liver, smaller adipocytes, and significantly better inflammatory findings in the small intestine. The concentrations of short-chain fatty acids (SCFAs), such as acetic acid, propanoic acid, and butanoic acid, in the serum, feces, and white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. In flow cytometry experiments, group 3 innate lymphoid cell (ILC3) counts in the lamina propria of the small intestine and ILC2 counts in the white adipose tissue of the Ery group were markedly higher than those in the Ctrl group. Quantitative real-time reverse transcription polymerase chain reaction analyses showed that the Il-22 expression in the small intestine of the Ery group was markedly higher than that in the Ctrl group. CONCLUSIONS: Erythritol markedly decreased metabolic disorders such as diet-induced obesity, glucose intolerance, dyslipidemia, and fat accumulation in the mouse liver by increasing SCFAs and modulating innate immunity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eritritol/farmacologia , Intolerância à Glucose/dietoterapia , Imunidade Inata/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Eritritol/administração & dosagem , Ácidos Graxos Voláteis/sangue , Ácidos Graxos Voláteis/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Intolerância à Glucose/metabolismo , Imunidade Inata/genética , Inflamação/dietoterapia , Inflamação/genética , Inflamação/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Obesidade/genética , Obesidade/metabolismo
17.
Am J Respir Cell Mol Biol ; 65(3): 309-318, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34003734

RESUMO

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.


Assuntos
Imidazóis/farmacologia , Imunidade Inata/efeitos dos fármacos , Interleucinas/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Glicoproteínas de Membrana/agonistas , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/agonistas , Animais , Asma/genética , Asma/imunologia , Asma/patologia , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Quimiocina CCL24/genética , Quimiocina CCL24/imunologia , Eosinófilos/imunologia , Eosinófilos/patologia , Imunidade Inata/genética , Inflamação/genética , Inflamação/imunologia , Interleucina-33/genética , Interleucina-33/imunologia , Interleucinas/genética , Pulmão/patologia , Linfócitos/patologia , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Interleucina/deficiência , Receptores de Interleucina/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia
18.
Scand J Gastroenterol ; 56(7): 855-861, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34034600

RESUMO

OBJECTIVES: Absence of a functional interferon-λ 4 (IFN-λ4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. MATERIALS AND METHODS: Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. RESULTS: The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-λ4 was absent (44% vs. 20% for IFNL4 TT/TTrs1368234815 and ΔGrs1368234815 respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-λ4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-λ4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p = .006). CONCLUSIONS: Absence of IFN-λ4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-λ4, reduced ITPase activity improved outcome.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Genótipo , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/genética , Hepatite C Crônica/tratamento farmacológico , Humanos , Interferons/uso terapêutico , Interleucinas/genética , Masculino , Polimorfismo de Nucleotídeo Único
19.
Fish Shellfish Immunol ; 115: 43-57, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33992768

RESUMO

IL-20 is a pleiotropic cytokine that belongs to the IL-10 family and plays an important biological role in tissue homeostasis and regulation of host immune defenses. IL-20 homologues have recently been discovered in fish, but their functions have not been studied. In this study, an IL-20 like (IL-20L) cytokine was cloned in grass carp (Ctenopharyngodon idella) and its bioactivities were investigated. Expression analysis showed that the CiIL-20L gene was constitutively expressed in tissues with the highest expression detected in the head kidney. It was upregulated in the head kidney after infection with Flavobactrium columnare (F. cloumnare) and grass carp reovirus II (GCRV II). The recombinant CiIL-20L produced in E. coli cells was shown to be effective in inducing the expression of Th cytokine genes (IFN-γ, IL-4/13A, IL-4/13B and IL-10), macrophage marker genes (arginase 2, IRF4, KLF4 and SOCS3) and inflammatory genes (IL-1ß, IL-6, IL-8 and TNFα) in the head kidney leukocytes when stimulated at 12 h. Long term culture (6 days) of head kidney macrophages in the presence of CiIL-20L leads to high expression of IRF4, TGFß1 and arginase 2. Our data suggest that IL-20 may play regulatory roles in promoting Th responses, macrophage differentiation and inflammation.


Assuntos
Carpas/genética , Carpas/imunologia , Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Interleucinas/genética , Interleucinas/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Proteínas de Peixes/química , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Infecções por Flavobacteriaceae/imunologia , Infecções por Flavobacteriaceae/veterinária , Flavobacterium/fisiologia , Perfilação da Expressão Gênica/veterinária , Interleucinas/química , Filogenia , Reoviridae/fisiologia , Infecções por Reoviridae/imunologia , Infecções por Reoviridae/veterinária , Alinhamento de Sequência/veterinária
20.
J Int Med Res ; 49(5): 3000605211019187, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34044633

RESUMO

OBJECTIVE: Abnormal B cell lymphoma-2 (Bcl-2) and interleukin-19 (IL-19) expression is closely related to systemic lupus erythematosus (SLE) pathogenesis. We aimed to determine whether BCL2 polymorphisms and a single nucleotide polymorphism (SNP) of IL19 are significantly associated with SLE susceptibility and if this is affected by synergism between IL19 and BCL2 genotypes. METHODS: This observational cohort study randomly enrolled 150 patients with SLE and 150 healthy controls. Major BCL2 and IL19 allele and genotype distributions were examined in the two groups. The IL19 SNP rs2243188 was determined using the TaqMan-MGB probe method. The synergistic effect between BCL2 and IL19 and clinical symptoms of SLE was also analyzed. RESULTS: The distribution of major BCL2 genotypes and common BCL2 alleles, especially for genotypes 191, 193, and 197, differed significantly between patients and controls. A significant difference in the dominant genetic model was also observed between groups, but not in the recessive model. The risk of disease in individuals who carried both 195-bp BCL2 and 138-bp IL19 susceptibility alleles was higher than in those carrying either allele alone. CONCLUSIONS: This preliminary study suggested that BCL2 polymorphisms and the IL19 SNP rs2243188 are closely related to the pathogenesis of SLE.


Assuntos
Lúpus Eritematoso Sistêmico , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Interleucinas/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética
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