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1.
Signal Transduct Target Ther ; 6(1): 189, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980808

RESUMO

Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.


Assuntos
/metabolismo , Exossomos/metabolismo , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , /genética , Animais , Chlorocebus aethiops , Exossomos/genética , Exossomos/virologia , Células HEK293 , Humanos , Camundongos , Camundongos Transgênicos , Células Vero
2.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33376202

RESUMO

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies (n NationMS = 946, n BIONAT = 990). Additionally, effect-modification by medication and photosensitivity-associated MC1R variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-ß-treated patients. In carriers of MC1R:rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.


Assuntos
Monócitos/efeitos da radiação , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Receptor Tipo 1 de Melanocortina/genética , Transcriptoma/efeitos da radiação , Vitamina D/sangue , Linfócitos B/efeitos da radiação , Estudos de Coortes , Feminino , Variação Genética , Genótipo , Humanos , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Esclerose Múltipla/patologia , Esclerose Múltipla/radioterapia , Fenótipo , Fototerapia , Recidiva , Índice de Gravidade de Doença , Luz Solar , Linfócitos T/metabolismo , Linfócitos T/efeitos da radiação , Transcriptoma/genética
3.
Front Immunol ; 11: 578648, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33362764

RESUMO

Gut microbiota has emerged as an important environmental factor in the pathobiology of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Both genetic and environmental factors have been shown to play an important role in MS. Among genetic factors, the human leukocyte antigen (HLA) class II allele such as HLA-DR2, DR3, DR4, DQ6, and DQ8 show the association with the MS. We have previously used transgenic mice expressing MS susceptible HLA class II allele such as HLA-DR2, DR3, DQ6, and DQ8 to validate significance of HLA alleles in MS. Although environmental factors contribute to 2/3 of MS risk, less is known about them. Gut microbiota is emerging as an imporatnt environmental factor in MS pathogenesis. We and others have shown that MS patients have distinct gut microbiota compared to healthy control (HC) with a lower abundance of Prevotella. Additionally, the abundance of Prevotella increased in patients receiving disease-modifying therapies (DMTs) such as Copaxone and/or Interferon-beta (IFNß). We have previously identified a specific strain of Prevotella (Prevotella histicola), which can suppress experimental autoimmune encephalomyelitis (EAE) disease in HLA-DR3.DQ8 transgenic mice. Since Interferon-ß-1b [IFNß (Betaseron)] is a major DMTs used in MS patients, we hypothesized that treatment with the combination of P. histicola and IFNß would have an additive effect on the disease suppression. We observed that treatment with P. histicola suppressed disease as effectively as IFNß. Surprisingly, the combination of P. histicola and IFNß was not more effective than either treatment alone. P. histicola alone or in combination with IFNß increased the frequency and number of CD4+FoxP3+ regulatory T cells in the gut-associated lymphoid tissue (GALT). Treatment with P. histicola alone, IFNß alone, and in the combination decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4+ T cells in the CNS. Additionally, P. histicola alone or IFNß alone or the combination treatments decreased CNS pathology, characterized by reduced microglia and astrocytic activation. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as effectively as commonly used MS drug IFNß and may provide an alternative treatment option for MS patients.


Assuntos
Anti-Inflamatórios/farmacologia , Encefalomielite Autoimune Experimental/prevenção & controle , Microbioma Gastrointestinal , Interferon beta/farmacologia , Intestinos/microbiologia , Prevotella/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Astrócitos/metabolismo , Astrócitos/microbiologia , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/microbiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/microbiologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/microbiologia , Masculino , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Microglia/microbiologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia
4.
Front Immunol ; 11: 566781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343562

RESUMO

IFN-ß treatment is a commonly used therapy for relapsing-remitting multiple sclerosis (MS), while vitamin D deficiency correlates with an increased risk of MS and/or its activity. MS is a demyelinating chronic inflammatory disease of the central nervous system, in which activated T lymphocytes play a major role, and may represent direct targets of IFN-ß and vitamin D activities. However, the underlying mechanism of action of vitamin D and IFN-ß, alone or in combination, remains incompletely understood, especially when considering their direct effects on the ability of T lymphocytes to produce inflammatory cytokines. We profiled the expression of immune-related genes and microRNAs in primary human T lymphocytes in response to vitamin D and IFN-ß, and we dissected the impact of these treatments on cytokine production and T cell proliferation. We found that the treatments influenced primarily memory T cell plasticity, rather than polarization toward a stable phenotype. Moreover, our data revealed extensive reprogramming of the transcriptional output of primary T cells in response to vitamin D and IFN-ß and provide the bases for further mechanistic insights into these commonly used treatments.


Assuntos
Interferon beta/farmacologia , Linfócitos T/efeitos dos fármacos , Vitamina D/farmacologia , Vitaminas/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Linfócitos T/imunologia
5.
PLoS Pathog ; 16(9): e1008773, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32881988

RESUMO

Japanese encephalitis virus (JEV) genotype I (GI) replicates more efficiently than genotype III (GIII) in birds, and this difference is considered to be one of the reasons for the JEV genotype shift. In this study, we utilized duck embryo fibroblasts and domestic ducklings as in vitro and in vivo models of a JEV amplifying avian host to identify the viral determinants of the differing replication efficiency between the GI and GIII strains in birds. GI strains induced significantly lower levels of interferon (IFN)-α and ß production than GIII strains, an effect orrelated with the enhanced replication efficiency of GI strains over GIII strains. By using a series of chimeric viruses with exchange of viral structural and non-structural (NS) proteins, we identified NS5 as the viral determinant of the differences in IFN-α and ß induction and replication efficiency between the GI and III strains. NS5 inhibited IFN-α and ß production induced by poly(I:C) stimulation and harbored 11 amino acid variations, of which the NS5-V372A and NS5-H386Y variations were identified to co-contribute to the differences in IFN-α and ß induction and replication efficiency between the strains. The NS5-V372A and NS5-H386Y variations resulted in alterations in the number of hydrogen bonds formed with neighboring residues, which were associated with the different ability of the GI and GIII strains to inhibit IFN-α and ß production. Our findings indicated that the NS5-V372A and NS5-H386Y variations enabled GI strains to inhibit IFN-α and ß production more efficiently than GIII strains for antagonism of the IFN-I mediated antiviral response, thereby leading to the replication and host adaption advantages of GI strains over GIII strains in birds. These findings provide new insight into the molecular basis of the JEV genotype shift.


Assuntos
Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/imunologia , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Mutação , Proteínas não Estruturais Virais/genética , Replicação Viral/genética , Animais , Antivirais/farmacologia , Patos , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Vírus da Encefalite Japonesa (Espécie)/genética , Encefalite Japonesa/tratamento farmacológico , Encefalite Japonesa/virologia , Interações Hospedeiro-Patógeno , Camundongos , Ligação Proteica , Suínos , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
6.
Nat Commun ; 11(1): 3810, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32733001

RESUMO

The pandemic of COVID-19 has posed an unprecedented threat to global public health. However, the interplay between the viral pathogen of COVID-19, SARS-CoV-2, and host innate immunity is poorly understood. Here we show that SARS-CoV-2 induces overt but delayed type-I interferon (IFN) responses. By screening 23 viral proteins, we find that SARS-CoV-2 NSP1, NSP3, NSP12, NSP13, NSP14, ORF3, ORF6 and M protein inhibit Sendai virus-induced IFN-ß promoter activation, whereas NSP2 and S protein exert opposite effects. Further analyses suggest that ORF6 inhibits both type I IFN production and downstream signaling, and that the C-terminus region of ORF6 is critical for its antagonistic effect. Finally, we find that IFN-ß treatment effectively blocks SARS-CoV-2 replication. In summary, our study shows that SARS-CoV-2 perturbs host innate immune response via both its structural and nonstructural proteins, and thus provides insights into the pathogenesis of SARS-CoV-2.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Evasão da Resposta Imune , Interferon Tipo I/metabolismo , Pneumonia Viral/virologia , Transdução de Sinais , Betacoronavirus/genética , Betacoronavirus/imunologia , Betacoronavirus/metabolismo , Linhagem Celular , Infecções por Coronavirus/imunologia , Humanos , Imunidade Inata , Interferon beta/genética , Interferon beta/metabolismo , Interferon beta/farmacologia , Mutação , Fases de Leitura Aberta , Pandemias , Pneumonia Viral/imunologia , Regiões Promotoras Genéticas , Transdução de Sinais/efeitos dos fármacos , Proteínas Virais/genética , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos
7.
J Infect ; 81(4): e1-e10, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32707230

RESUMO

OBJECTIVES: Respiratory and intestinal tract are two primary target organs of SARS-CoV-2 infection. However, detailed characterization of the host-virus interplay in infected human lung and intestinal epithelial cells is lacking. METHODS: We utilized immunofluorescence assays, flow cytometry, and RT-qPCR to delineate the virological features and the innate immune response of the host cells against SARS-CoV-2 infection in two prototype human cell lines representing the human lung (Calu3) and intestinal (Caco2) epithelium when compared with SARS-CoV. RESULTS: Lung epithelial cells were significantly more susceptible to SARS-CoV-2 compared to SARS-CoV. However, SARS-CoV-2 infection induced an attenuated pro-inflammatory cytokines/chemokines induction and type I and type II IFN responses. A single dose of 10 U/mL interferon-ß (IFNß) pretreatment potently protected both Calu3 and Caco2 against SARS-CoV-2 infection. Interestingly, SARS-CoV-2 was more sensitive to the pretreatment with IFNß and IFN inducer than SARS-CoV in Calu3. CONCLUSIONS: Despite robust infection in both human lung and intestinal epithelial cells, SARS-CoV-2 could attenuate the virus-induced pro-inflammatory response and IFN response. Pre-activation of the type I IFN signaling pathway primed a highly efficient antiviral response in the host against SARS-CoV-2 infection, which could serve as a potential therapeutic and prophylactic maneuver to COVID-19 patients.


Assuntos
Infecções por Coronavirus/imunologia , Indutores de Interferon/farmacologia , Interferon beta/farmacologia , Mucosa Intestinal/imunologia , Pneumonia Viral/imunologia , Mucosa Respiratória/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/farmacologia , Betacoronavirus/imunologia , Células CACO-2 , Linhagem Celular Tumoral , Infecções por Coronavirus/tratamento farmacológico , Células Epiteliais/virologia , Humanos , Imunidade Inata , Pulmão/imunologia , Pandemias , Vírus da SARS/imunologia
9.
Science ; 369(6504): 712-717, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32527928

RESUMO

Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-ß) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-ß responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).


Assuntos
Células Epiteliais Alveolares/patologia , Citocinas/metabolismo , Interferon Tipo I/metabolismo , Interferons/metabolismo , Pulmão/patologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Células Epiteliais Alveolares/imunologia , Animais , Apoptose , Líquido da Lavagem Broncoalveolar/imunologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Citocinas/administração & dosagem , Citocinas/imunologia , Feminino , Vírus da Influenza A Subtipo H3N2 , Interferon Tipo I/administração & dosagem , Interferon Tipo I/farmacologia , Interferon-alfa/administração & dosagem , Interferon-alfa/metabolismo , Interferon-alfa/farmacologia , Interferon beta/administração & dosagem , Interferon beta/metabolismo , Interferon beta/farmacologia , Interferons/administração & dosagem , Interferons/farmacologia , Masculino , Camundongos , Infecções por Orthomyxoviridae/metabolismo , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
10.
Neurology ; 94(22): e2373-e2383, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430312

RESUMO

OBJECTIVE: Disease-modifying treatments (DMTs) are the gold standard for slowing disability progression in multiple sclerosis (MS), but their effects on cognitive impairment, a key symptom of the disease, are mostly unknown. We conducted a systematic review and meta-analysis to evaluate the differential effects of DMTs on cognitive test performance in relapsing-remitting MS (RRMS). METHODS: PubMed, Scopus, and Cochrane Library were searched for studies reporting longitudinal cognitive performance data related to all major DMTs. The standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used as the main effect size measure. RESULTS: Forty-four studies, including 55 distinct MS patient samples, were found eligible for the systematic review. Twenty-five studies were related to platform therapies (mainly ß-interferon [n = 17] and glatiramer acetate [n = 4]), whereas 22 studies were related to escalation therapies (mainly natalizumab [n = 14] and fingolimod [n = 6]). Reported data were mostly confined to the cognitive domain processing speed. A meta-analysis including 41 studies and 7,131 patients revealed a small to moderate positive effect on cognitive test performance of DMTs in general (g = 0.27, 95% confidence interval [CI] = [0.21-0.33]), but no statistically significant differences between platform (g = 0.27, 95% CI = [0.18-0.35]) and escalation therapies (g = 0.28, 95% CI = [0.19-0.37]) or between any single DMT and ß-interferon. CONCLUSIONS: DMTs are effective in improving cognitive test performance in RRMS, but a treatment escalation mainly to amend cognition is not supported by the current evidence. Given the multitude of DMTs and their widespread use, the available data regarding differential treatment effects on cognitive impairment are remarkably scant. Clinical drug trials that use more extensive cognitive outcome measures are urgently needed.


Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Imunossupressores/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Cognição/fisiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/psicologia , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/farmacologia , Acetato de Glatiramer/uso terapêutico , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/farmacologia , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Esclerose Múltipla Recidivante-Remitente/psicologia , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
11.
Antiviral Res ; 179: 104811, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32360182

RESUMO

There is an urgent need to identify antivirals to curtail the COVID-19 pandemic. Herein, we report the sensitivity of SARS-CoV-2 to recombinant human interferons α and ß (IFNα/ß). Treatment with IFN-α or IFN-ß at a concentration of 50 international units (IU) per milliliter reduces viral titers by 3.4 log or over 4 log, respectively, in Vero cells. The EC50 of IFN-α and IFN-ß treatment is 1.35 IU/ml and 0.76 IU/ml, respectively, in Vero cells. These results suggest that SARS-CoV-2 is more sensitive than many other human pathogenic viruses, including SARS-CoV. Overall, our results demonstrate the potential efficacy of human Type I IFN in suppressing SARS-CoV-2 infection, a finding which could inform future treatment options for COVID-19.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Interferon Tipo I/farmacologia , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Animais , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Imunidade Inata , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Proteínas Recombinantes/farmacologia , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
12.
Georgian Med News ; (298): 84-88, 2020 Jan.
Artigo em Russo | MEDLINE | ID: mdl-32141856

RESUMO

About 30-40% of multiple sclerosis (MS) patients treated with interferon-beta (IFN-ß) develop neutralizing antibodies (NABs) to IFN-ß. NABs reduce bioavailability of IFN-ß, which leads to a decrease in the therapy effectiveness. The introduction of IFN-ß induce production of several proteins, which are used as markers of the therapy effectiveness. In this study, we assessed the prognostic significance of MS activity biomarkers in relation to the clinical data of MS patients treated with IFN-ß. The study involved 30 MS patients receiving IFN-ß. The average duration of therapy was 3.5 (3.4-5.3) years. The study showed the prevalence of NAbs formation in MS patients was 13% of cases, a year later - 30%. The level of viperin in patients without exacerbations during the observation period was lower than in patients with exacerbations. The study revealed the prognostic significance of viperin in relation to the frequency of exacerbations: viperin concentration above 0.2 ng / ml is a risk factor for exacerbation of MS. The results of this study suggest that viperin concentration in the serum could be used a prognostic marker in MS patients treated with interferons.


Assuntos
Interferon beta/farmacologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Anticorpos/análise , Anticorpos/sangue , Anticorpos Neutralizantes , Biomarcadores/análise , Biomarcadores/sangue , República da Geórgia/epidemiologia , Humanos , Interferon beta/efeitos adversos , Interferon beta/uso terapêutico , Esclerose Múltipla/sangue , Esclerose Múltipla/epidemiologia , Prevalência , Prognóstico , Resultado do Tratamento
13.
Biochem Biophys Res Commun ; 526(1): 253-260, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32204916

RESUMO

Ischaemic heart disease is one of the leading causes of death. Protease-activated receptor 2 (PAR2) is widely expressed within the cardiovascular system and is known to mediate inflammatory processes in various immunocytes, such as macrophages, mastocytes and neutrophils. Here, we investigated whether activating macrophage PAR2 modulates cardiac remodelling in a murine model of myocardial infarction. Myocardial infarction was produced by the permanent ligation of the left anterior descending coronary artery (LAD) in C57BL/6J background wild-type (WT) mice transplanted with bone marrow from WT or PAR2 knockout (PAR2 KO) mice. Hematopoietic deficiency of PAR2 had improvement of left ventricular systolic dysfunction and dilatation and decreased fibrosis deposition in remote zone at 1 week after LAD ligation. Inactivation of PAR2 also led to less recruitment of macrophages in myocardium, which was accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, cultured cardiac fibroblasts (CFs) were activated and showed a fibrotic phenotype after being co-cultured in medium containing PAR2-activating macrophage, which enhances interferon-beta (INF-ß) expression. The beneficial effects of macrophages with INF-ß neutralisation or PAR2-deletion ameliorates the JAK/STAT3 pathway in CFs, which might be attributed to CF activation. These data suggest that macrophage-derived IFN-ß plays a crucial role in adverse cardiac remodelling after myocardial infarction, at least in part, through a PAR2-dependent mechanism.


Assuntos
Linhagem da Célula , Células-Tronco Hematopoéticas/patologia , Inflamação/patologia , Infarto do Miocárdio/patologia , Receptor PAR-2/deficiência , Animais , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Interferon beta/farmacologia , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isquemia Miocárdica/patologia , Miocárdio/patologia , Receptor PAR-2/metabolismo
14.
J Gastroenterol Hepatol ; 35(8): 1426-1436, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31951295

RESUMO

BACKGROUND AND AIM: Interferon-stimulated gene 20 (ISG20) is an interferon-inducible exonuclease that inhibits the replication of several RNA viruses. In patients with chronic hepatitis B, ISG20 expression is related to the interferon-α treatment response. However, the molecular mechanism of ISG20-mediated anti-hepatitis B virus (HBV) activity is unclear. METHODS: We have investigated the effect of ISG20 on antiviral activity to address that. The life cycle of HBV was analyzed by the ectopic expression of ISG20 in HepG2 and HepG2-NTCP cells. Finally, to provide physiological relevance of our study, the expression of ISG20 from chronic hepatitis B patients was examined. RESULTS: Interferon-stimulated gene 20 was mainly induced by interferon-ß and dramatically inhibited HBV replication. In addition, ISG20 decreased HBV gene expression and transcription. Although ISG20 inhibited HBV replication by reducing viral enhancer activity, the expression of transcription factors that bind the HBV enhancer was not affected. Particularly, ISG20 suppressed HBV enhancer activity by binding to the enhancer II and core promoter (EnhII/Cp) region. CONCLUSION: Our findings suggest that ISG20 exerts the anti-HBV activity by acting as a putative repressor binding to the HBV EnhII/Cp region.


Assuntos
Exorribonucleases/genética , Exorribonucleases/metabolismo , Expressão Gênica , Vírus da Hepatite B/genética , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/genética , Interferon-alfa/uso terapêutico , Interferon beta/uso terapêutico , Ativação Viral/genética , Exorribonucleases/fisiologia , Células Hep G2 , Humanos , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Replicação Viral/genética
15.
J Neuroimmunol ; 339: 577113, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31778850

RESUMO

Our work consists of a pilot study to characterize circulating Th/c1, Th/c2, Th/c17, Treg and Tfh-like populations and IL-17 serum levels of relapsing-remitting (RR) MS patients treated with IFN-ß, compared with healthy controls. In remission RRMS patients, we observe increased Th/c17 cells frequency committed to a Th1 profile and increased soluble IL-17 levels. Moreover, a shift toward Th/c2 with reduction of Tc1 cells and decrease in effector/terminal differentiated compartment of Th1 cells were also observed. Despite RRMS patients being an inactive disease phase, IL-17 and Th/c17 cells seemed to contribute to perpetuating chronic inflammation, besides the altered ratio Th1/Th2.


Assuntos
Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Adulto , Feminino , Humanos , Fatores Imunológicos/farmacologia , Interferon beta/farmacologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Resultado do Tratamento
16.
J Neuroimmunol ; 338: 577106, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31715458

RESUMO

Recent studies identified that interferon beta (IFN-ß) treatment skews B-cells towards a regulatory phenotype in multiple sclerosis. To assess B cell involvement during IFN-ß therapy, we compared IFN-ß treatment in a B cell-independent model and a B cell-dependent model of experimental autoimmune encephalomyelitis (EAE). We show that in B cell-independent EAE, IFN-ß ameliorates neuroinflammation. Conversely, in B cell-dependent EAE, IFN-ß has no effect on disease. Effective IFN-ß therapy in B cell-independent EAE was associated with reduced inflammatory T cells in the CNS and skewed splenic B cells towards an immature population and away from a germinal center population. These immune cell populations were unchanged in B cell-dependent EAE. Finally, we found that IFN-ß increased marginal zone B cells in both EAE models. These findings indicate that B cell function impacts IFN-ß efficacy during neuroinflammation.


Assuntos
Linfócitos B/fisiologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Interferon beta/uso terapêutico , Animais , Linfócitos B/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Feminino , Interferon beta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia
17.
J Neuroimmunol ; 338: 577082, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31707103

RESUMO

ß2-adrenoceptors are G-protein coupled receptors expressed on both astrocytes and microglia that play a key role in mediating the anti-inflammatory actions of noradrenaline in the CNS. Here the effect of an inflammatory stimulus (LPS + IFN-γ) was examined on glial ß2-adrenoceptor expression and function. Exposure of glia to LPS + IFN-γ decreased ß2-adrenoceptor mRNA and agonist-stimulated production of the intracellular second messenger cAMP. Pre-treatment with the synthetic glucocorticoid and potent anti-inflammatory agent dexamethasone prevented the LPS + IFN-γ-induced suppression of ß2-adrenoceptor mRNA expression. These results raise the possibility that inflammation-mediated ß2-adrenoceptor downregulation in glia may dampen the innate anti-inflammatory properties of noradrenaline in the CNS.


Assuntos
Dexametasona/farmacologia , Inflamação/metabolismo , Neuroglia/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Animais , Células Cultivadas , AMP Cíclico/biossíntese , Interferon beta/farmacologia , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Neuroglia/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/fisiologia , Fator de Necrose Tumoral alfa/biossíntese
18.
Neuroimage Clin ; 24: 102020, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31734534

RESUMO

Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders. We followed a symptom dimensional approach by simultaneously investigating two distinct symptom domains of depressiveness: negative affect (amygdala) and appetitive motivation (ventral striatum). In these early phases of IFN treatment we detected a selective change in neural substrates of appetitive motivation, consistent with the predominant symptomatic change recorded in psychopathology ratings. In contrast, the fMRI phenotype of negative affect, which is known to characterize disorders of affect involving anxiety and depressiveness as well as individual vulnerability to depression, was unchanged after treatment. These findings suggest that IFN may induce an affective syndrome through a mechanism involving down-regulation of appetitive motivation.


Assuntos
Afeto , Tonsila do Cerebelo , Ansiedade , Depressão , Fatores Imunológicos/farmacologia , Interferon beta/farmacologia , Motivação , Recompensa , Estriado Ventral , Adolescente , Adulto , Afeto/efeitos dos fármacos , Afeto/fisiologia , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Ansiedade/induzido quimicamente , Ansiedade/diagnóstico por imagem , Ansiedade/fisiopatologia , Depressão/induzido quimicamente , Depressão/diagnóstico por imagem , Depressão/fisiopatologia , Expressão Facial , Reconhecimento Facial/efeitos dos fármacos , Reconhecimento Facial/fisiologia , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Interferon beta/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Motivação/efeitos dos fármacos , Motivação/fisiologia , Estriado Ventral/diagnóstico por imagem , Estriado Ventral/efeitos dos fármacos , Estriado Ventral/fisiologia , Adulto Jovem
19.
Immunol Lett ; 216: 63-69, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31589897

RESUMO

Multiple Sclerosis (MS) is an immune-mediated and neurodegenerative disease of central nervous system. Relapsing-remitting (RR)-MS occurring with acute attacks and remissions, is the most common clinical type of MS. There are different strategies applied in first-line treatment of RR-MS patients such as interferon-beta (IFN-ß) and glatiramer acetate. In this study, activating and inhibitory receptor expressions and interleukin (IL)-22 levels of NK cells were investigated in RR-MS patients with or without IFN-ß therapy. Activating receptor expression and IL-22 levels of NK cells were increased in RR-MS patients under IFN-ß therapy. Elevated NK cells with activating profile and increased IL-22 under IFN-ß therapy suggest that IFN-ß treatment might direct NK cells toward a pro-inflammatory status.


Assuntos
Fatores Imunológicos/farmacologia , Interferon beta/farmacologia , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Adolescente , Adulto , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígeno CD56/imunologia , Antígeno CD56/metabolismo , Resistência a Medicamentos/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Interleucinas/sangue , Interleucinas/imunologia , Interleucinas/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Resultado do Tratamento , Adulto Jovem
20.
Neurol Neuroimmunol Neuroinflamm ; 6(6): e622, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31582399

RESUMO

OBJECTIVE: To determine the effect of vitamin D3 on interferon-ß (IFN-ß) response and immune regulation in MS mononuclear cells (MNCs). METHODS: MNCs from 126 subjects, including therapy-naive patients with different forms of MS, plus patients with MS receiving IFN-ß or glatiramer treatment, plus healthy controls were incubated in vitro with IFN-ß-1b ± vitamin D3 (calcitriol). Activation of the IFN-ß-induced transcription factor, p-Y-STAT1, and antiviral myxovirus A (MxA) protein was measured with flow cytometry and Western blots; serum proteins were measured with a customized 31-protein multiplex assay. RESULTS: Vitamin D enhanced in vitro IFN responses, as measured by induction of p-Y-STAT1 and MxA in MNCs, T cells, and monocytes. Vitamin D augmentation of IFN responses was seen in untreated and in IFN-ß-1b-treated MS. The combination of vitamin D plus IFN-ß reduced Th1 and Th17 cytokines, and increased Th2 responses, reversing the effect of IFN-ß alone. Exacerbations and progression in untreated patients reduced the vitamin D enhancement of IFN responses. Vitamin D had less effect on IFN response in clinically stable glatiramer-treated than in IFN-ß-treated patients. CONCLUSION: Vitamin D enhances IFN-ß induction of multiple proteins and also reverses the Th1/Th2 bias in MS seen with IFN-ß alone. The combination of vitamin D and IFN-ß has potential benefit in ameliorating MS.


Assuntos
Colecalciferol/farmacologia , Fatores Imunológicos/farmacologia , Interferon beta/efeitos dos fármacos , Interferon beta/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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