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1.
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
2.
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
3.
EBioMedicine ; 49: 269-283, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31648992

RESUMO

BACKGROUND: In multiple sclerosis (MS), immune up-regulation is coupled to subnormal immune response to interferon-ß (IFN-ß) and low serum IFN-ß levels. The relationship between the defect in IFN signalling and acute and long-term effects of IFN-ß on gene expression in MS is inadequately understood. METHODS: We profiled IFN-ß-induced transcriptome shifts, using high-resolution microarrays on 227 mononuclear cell samples from IFN-ß-treated MS Complete Responders (CR) stable for five years, and stable and active Partial Responders (PR), stable and active untreated MS, and healthy controls. FINDINGS: IFN-ß injection induced short-term changes in 1,200 genes compared to baseline expression after 4-day IFN washout. Pre-injection after washout, and in response to IFN-ß injections, PR more frequently had abnormal gene expression than CR. Surprisingly, short-term IFN-ß induced little shift in Th1/Th17/Th2 gene expression, but up-regulated immune-inhibitory genes (ILT, IDO1, PD-L1). Expression of 8,800 genes was dysregulated in therapy-naïve compared to IFN-ß-treated patients. These long-term changes in protein-coding and long non-coding RNAs affect immunity, synaptic transmission, and CNS cell survival, and correct the disordered therapy-naïve transcriptome to near-normal. In keeping with its impact on clinical course and brain repair in MS, long-term IFN-ß treatment reversed the overexpression of proinflammatory and MMP genes, while enhancing genes involved in the oligodendroglia-protective integrated stress response, neuroprotection, and immunoregulation. In the rectified long-term signature, 277 transcripts differed between stable PR and CR patients. INTERPRETATION: IFN-ß had minimal short-term effects on Th1 and Th2 pathways, but long-term it corrected gene dysregulation and induced immunoregulatory and neuroprotective genes. These data offer new biomarkers for IFN-ß responsiveness. FUNDING: Unrestricted grants from the US National MS Society, NMSS RG#4509A, and Bayer Pharmaceuticals.


Assuntos
Interferon beta/farmacologia , Esclerose Múltipla/genética , Neuroproteção/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Neuroproteção/efeitos dos fármacos , Fases de Leitura Aberta/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fatores de Tempo , Transcriptoma/genética
4.
Oncol Rep ; 42(6): 2635-2643, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638255

RESUMO

Tumor necrosis factor­related apoptosis­inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) family, induces apoptosis in cancer cells by binding to its receptors, death receptor 4 (DR4) and DR5, without affecting normal cells, and is therefore considered to be a promising antitumor agent for use in cancer treatment. However, several studies have indicated that most glioma cell lines display resistance to TRAIL­induced apoptosis. To overcome such resistance and to improve the efficacy of TRAIL­based therapies, identification of ideal agents for combinational treatment is important for achieving rational clinical treatment in glioblastoma patients. The main aim of this study was to investigate whether interferon­ß (IFN­ß) (with its pleiotropic antitumor activities) could sensitize malignant glioma cells to TRAIL­induced apoptosis using glioma cell lines. TRAIL exhibited a dose­dependent antitumor effect in all of the 7 types of malignant glioma cell lines, although the intensity of the effect varied among the cell lines. In addition, combined treatment with TRAIL (low clinical dose: 1 ng/ml) and IFN­ß (clinically relevant concentration: 10 IU/ml) in A­172, AM­38, T98G, U­138MG and U­251MG demonstrated a more marked antitumor effect than TRAIL alone. Furthermore, the antitumor effect of the combined treatment with TRAIL and IFN­ß may be enhanced via an extrinsic apoptotic system, and upregulation of DR5 was revealed to play an important role in this process in U­138MG cells. These findings provide an experimental basis to suggest that combined treatment with TRAIL and IFN­ß may offer a new therapeutic strategy for malignant gliomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Interferon beta/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Interferon beta/uso terapêutico , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Regulação para Cima/efeitos dos fármacos
5.
Artigo em Inglês | MEDLINE | ID: mdl-31152860

RESUMO

Neuronal apoptosis and impaired hippocampal neurogenesis are major players in cognitive/memory dysfunctions including Alzheimer's disease (AD). Interferon beta (IFNß) is a cytokine with anti-apoptotic and neuroprotective properties on the central nervous system (CNS) cells which specifically affects neural progenitor cells (NPCs) even in the adult brain. In this study, we examined the effect of IFNß on memory impairment as well as hippocampal neurogenesis and apoptosis in a rat model of AD. AD model was induced by lentiviral-mediated overexpression of mutant APP in the hippocampus of adult rats. Intranasal (IN) administration of IFNß (0.5 µg/kg and 1 µg/kg doses) was started from day 23 after virus injection and continued every other day to the final day of experiments. The expression levels of APP, neurogenesis (Nestin, Ki67, DCX, and Reelin) and apoptosis (Bax/Bcl-2 ratio, cleaved-caspase-3 and seladin-1) markers were evaluated by immunohistochemistry, real-time PCR, immunofluorescence and western blotting. Moreover, thioflavin T and Nissl stainings were used to assess Aß plaque levels and neuronal degeneration in the hippocampus, respectively. Our results showed that IFNß treatment reduced APP expression and Aß plaque formation, and concomitantly ameliorated spatial learning and memory deficits examined in Y-maze and Morris water maze tests. Moreover, in parallel with reducing apoptosis and neural loss in the hippocampal subfields, IFNß decreased ectopic neurogenesis in the CA1 and CA3 regions of the AD rat hippocampus. However, IFNß increased neurogenesis in the dentate gyrus neurogenic niche. Our findings suggest that IFNß exerts neuroprotective effects at least partly by inhibition of apoptosis and modulation of neurogenesis. Taken together, IFNß can be a promising therapeutic approach to improve cognitive performance in AD-like neurodegenerative context.


Assuntos
Doença de Alzheimer/prevenção & controle , Apoptose/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Interferon beta/farmacologia , Transtornos da Memória/prevenção & controle , Neurogênese/efeitos dos fármacos , Administração Intranasal , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/efeitos adversos , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Vetores Genéticos , Interferon beta/administração & dosagem , Lentivirus , Masculino , Mutação , Placa Amiloide/patologia , Ratos
6.
Breast Cancer Res ; 21(1): 54, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036052

RESUMO

BACKGROUND: Highly aggressive, metastatic and therapeutically resistant triple-negative breast cancers (TNBCs) are often enriched for cancer stem cells (CSC). Cytokines within the breast tumor microenvironment (TME) influence the CSC state by regulating tumor cell differentiation programs. Two prevalent breast TME cytokines are oncostatin-M (OSM) and interferon-ß (IFN-ß). OSM is a member of the IL-6 family of cytokines and can drive the de-differentiation of TNBC cells to a highly aggressive CSC state. Conversely, IFN-ß induces the differentiation of TNBC, resulting in the repression of CSC properties. Here, we assess how these breast TME cytokines influence CSC plasticity and clinical outcome. METHODS: Using transformed human mammary epithelial cell (HMEC) and TNBC cell models, we assessed the CSC markers and properties following exposure to OSM and/or IFN-ß. CSC markers included CD24, CD44, and SNAIL; CSC properties included tumor sphere formation, migratory capacity, and tumor initiation. RESULTS: There are three major findings from our study. First, exposure of purified, non-CSC to IFN-ß prevents OSM-mediated CD44 and SNAIL expression and represses tumor sphere formation and migratory capacity. Second, during OSM-induced de-differentiation, OSM represses endogenous IFN-ß mRNA expression and autocrine/paracrine IFN-ß signaling. Restoring IFN-ß signaling to OSM-driven CSC re-engages IFN-ß-mediated differentiation by repressing OSM/STAT3/SMAD3-mediated SNAIL expression, tumor initiation, and growth. Finally, the therapeutic use of IFN-ß to treat OSM-driven tumors significantly suppresses tumor growth. CONCLUSIONS: Our findings suggest that the levels of IFN-ß and OSM in TNBC dictate the abundance of cells with a CSC phenotype. Indeed, TNBCs with elevated IFN-ß signaling have repressed CSC properties and a better clinical outcome. Conversely, TNBCs with elevated OSM signaling have a worse clinical outcome. Likewise, since OSM suppresses IFN-ß expression and signaling, our studies suggest that strategies to limit OSM signaling or activate IFN-ß signaling will disengage the de-differentiation programs responsible for the aggressiveness of TNBCs.


Assuntos
Interferon beta/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Oncostatina M/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
7.
Vet Microbiol ; 231: 139-146, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30955801

RESUMO

The recent emergence of highly pathogenic porcine reproductive and respiratory syndrome virus 1 (PRRSV-1) strains has caused severe economic losses. The biological elements defining virulence and pathogenicity are still unclear. In vitro characteristics using natural target cells of PRRSV provide important information to understand the basis of virulence at the cellular level, and provide a mean to reduce animal experimentations to achieve this goal. Here, we compared PRRSV strains from two geographically different regions, with varying in vivo characteristics, in terms of their interactions with monocyte-derived macrophages (MDMs). The strains included Lena and BOR59 from Belarus, and ILI6 from Russia, as well as PR11 and PR40, both from Italy. As a reference, we used a cell culture-adapted version of Lelystad, LVP. MDMs were pre-treated with IFNγ, IL-4 or IFNß, in order to understand responses in polarized and antiviral MDMs. In general, independent of the geographical origin, the strains with high virulence infected a higher percentage of MDMs and replicated to higher titers. These virulence-dependent differences were most pronounced when the MDMs had been treated with IFNß. Differentiation between intermediate and low virulent PRRSV was difficult, due to variations between different experiments, but LVP differed clearly from all field strains. IFNα and IL-10 were not detected in any experiment, but PR40 induced TNF and IL-1ß. Taken together, these results validate the MDM model to understand pathogenicity factors of PRRSV and confirm the importance of the escape from type I and II IFN-mediated effects for PRRSV virulence.


Assuntos
Macrófagos/virologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Animais , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Interleucina-10/farmacologia , Itália , Macrófagos/efeitos dos fármacos , Vírus da Síndrome Respiratória e Reprodutiva Suína/classificação , República de Belarus , Federação Russa , Suínos , Virulência
8.
Int J Oncol ; 54(5): 1864-1874, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864696

RESUMO

Malignant melanoma is a highly aggressive skin cancer that is highly resistant to chemotherapy. Adjuvant therapy is administered to patients with melanoma that possess no microscopic metastases or have a high risk of developing microscopic metastases. Methylating agents, including dacarbazine (DTIC) and temozolomide (TMZ), pegylated interferon (IFN)­α2b and interleukin­2 have been approved for adjuvant immuno­chemotherapy; however, unsatisfactory results have been reported following the administration of methylating agents. IFN­ß has been considered to be a signaling molecule with an important therapeutic potential in cancer. The aim of the present study was to elucidate whether antitumor effects could be augmented by the combination of TMZ and IFN­ß in malignant melanoma. We evaluated the efficacy of TMZ and IFN­ß by comparing O6­methylguanine­DNA transferase (MGMT)­proficient and ­deficient cells, as MGMT has been reported to be associated with the resistance to methylating agents. Cell viability was determined by counting living cells with a Coulter counter, and apoptosis was analyzed by dual staining with Annexin V Alexa Fluor® 488 and propidium iodide. The expression of proteins involved in the cell cycle, apoptosis and autophagy was evaluated by western blot analysis. The combined treatment with TMZ and IFN­ß suppressed cell proliferation and induced cell cycle arrest. We also demonstrated that a combination of TMZ and IFN­ß enhanced apoptosis and autophagy more efficiently compared with TMZ treatment alone. These findings suggest that antitumor activity may be potentiated by IFN­ß in combination with TMZ.


Assuntos
Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Interferon beta/farmacologia , Melanoma/genética , Temozolomida/farmacologia , Proteínas Supressoras de Tumor/genética , Autofagia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Melanoma/tratamento farmacológico , Melanoma/metabolismo
9.
J Exp Med ; 216(3): 621-637, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30723095

RESUMO

Ectopic lymphoid structures form in a wide range of inflammatory conditions, including infection, autoimmune disease, and cancer. In the context of infection, this response can be beneficial for the host: influenza A virus infection-induced pulmonary ectopic germinal centers give rise to more broadly cross-reactive antibody responses, thereby generating cross-strain protection. However, despite the ubiquity of ectopic lymphoid structures and their role in both health and disease, little is known about the mechanisms by which inflammation is able to convert a peripheral tissue into one that resembles a secondary lymphoid organ. Here, we show that type I IFN produced after viral infection can induce CXCL13 expression in a phenotypically distinct population of lung fibroblasts, driving CXCR5-dependent recruitment of B cells and initiating ectopic germinal center formation. This identifies type I IFN as a novel inducer of CXCL13, which, in combination with other stimuli, can promote lung remodeling, converting a nonlymphoid tissue into one permissive to functional tertiary lymphoid structure formation.


Assuntos
Quimiocina CXCL13/metabolismo , Centro Germinativo/patologia , Interferon Tipo I/metabolismo , Infecções por Orthomyxoviridae/patologia , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Quimiocina CXCL13/genética , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/virologia , Centro Germinativo/efeitos dos fármacos , Centro Germinativo/metabolismo , Interferon beta/farmacologia , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infecções por Orthomyxoviridae/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
10.
Neurobiol Dis ; 127: 13-31, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30798007

RESUMO

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the human central nervous system (CNS), mainly affecting young adults. Among the immunomodulatory disease modifying treatments approved up to date to treat MS, IFN-ß remains to be one of the most widely prescribed for the Relapsing-Remitting (RR) variant of the disease, although its mechanism of action is still partially understood. RR-MS variant is characterized by phases with increasing neurological symptoms (relapses) followed by periods of total or partial recovery (remissions), which implies the existence of immunomodulatory agents to promote the relapsing-to-remitting transition. Among these agents, it has been described the immunosuppressive role of a heterogeneous population of immature myeloid cells, namely the myeloid-derived suppressor cells (MDSCs) during the clinical course of the experimental autoimmune encephalomyelitis (EAE), the most used MS model to study RRMS. However, it is still unknown how the current MS disease modifying treatments, e.g. IFN- ß, affects to MDSCs number or activity. Our present results show that a single injection of IFN-ß at the onset of the clinical course reduces the severity of the EAE, enhancing the presence of MDSCs within the smaller demyelinated areas. Moreover, the single dose of IFN-ß promotes MDSC immunosuppressive activity both in vivo and in vitro, augmenting T cell apoptosis. Finally, we show that IFN-ß preserves MDSC immaturity, preventing their differentiation to mature and less suppressive myeloid cell subsets. Taking together, all these data add new insights into the mechanism of IFN-ß treatment in EAE and point to MDSCs as a putative endogenous mediator of its beneficial role in this animal model of MS.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Imunossupressores/uso terapêutico , Interferon beta/uso terapêutico , Células Supressoras Mieloides/efeitos dos fármacos , Animais , Encefalomielite Autoimune Experimental/imunologia , Imunossupressores/farmacologia , Interferon beta/farmacologia , Camundongos , Células Supressoras Mieloides/imunologia
11.
Nat Commun ; 10(1): 280, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655513

RESUMO

Although Zika virus (ZIKV) can be transmitted sexually and cause congenital birth defects, immune control mechanisms in the female reproductive tract (FRT) are not well characterized. Here we show that treatment of primary human vaginal and cervical epithelial cells with interferon (IFN)-α/ß or IFN-λ induces host defense transcriptional signatures and inhibits ZIKV infection. We also assess the effects of IFNs on intravaginal infection of the FRT using ovariectomized mice treated with reproductive hormones. We find that mice receiving estradiol are protected against intravaginal ZIKV infection, independently of IFN-α/ß or IFN-λ signaling. In contrast, mice lacking IFN-λ signaling sustain greater FRT infection when progesterone is administered. Exogenous IFN-λ treatment confers an antiviral effect when mice receive both estradiol and progesterone, but not progesterone alone. Our results identify a hormonal stage-dependent role for IFN-λ in controlling ZIKV infection in the FRT and suggest a path for minimizing sexual transmission of ZIKV in women.


Assuntos
Antivirais/farmacologia , Interleucinas/farmacologia , Doenças Virais Sexualmente Transmissíveis/prevenção & controle , Infecção por Zika virus/prevenção & controle , Zika virus/patogenicidade , Administração Intravaginal , Animais , Antivirais/uso terapêutico , Colo do Útero/citologia , Colo do Útero/virologia , Modelos Animais de Doenças , Células Epiteliais , Estradiol/farmacologia , Feminino , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Interferon beta/farmacologia , Interferon beta/uso terapêutico , Interleucinas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Progesterona/farmacologia , Doenças Virais Sexualmente Transmissíveis/imunologia , Doenças Virais Sexualmente Transmissíveis/transmissão , Doenças Virais Sexualmente Transmissíveis/virologia , Vagina/citologia , Vagina/virologia , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Zika virus/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
12.
Cell Death Dis ; 10(2): 85, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30692524

RESUMO

Administration of mesenchymal stem cells (MSC) ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), at both clinical and neuropathological levels. The therapeutic properties of MSC in EAE are mainly mediated by the modulation of pathogenic immune response, but other neurotropic effects, including decreased demyelination and axonal loss as well as promotion of tissue repair, play also a role. Properly controlled phase II clinical trials to explore the potential of MSC transplantation as a treatment for MS are underway. Interferon beta (IFNß) is an approved treatment for relapsing-remitting and secondary progressive MS. Here, we explored the possibility that IFNß might influence the therapeutic potential of MSC, in view of possible synergistic effects as add-on therapy. IFNß enhanced the immunomodulatory functions of MSC and induced the expression of secretory leukocyte protease inhibitor (Slpi) and hepatocyte growth factor (Hgf), two soluble mediators involved in immune and regenerative functions of MSC. At molecular level, IFNß induced a rapid and transient phosphorylation of STAT1 and STAT3, the transcription factors responsible for Slpi and Hgf induction. Concomitantly, IFNß dynamically affected the activity of mTOR, a key checkpoint in the control of metabolic pathways. Indeed, the impairment of mTOR activity observed early upon exposure to IFNß, was followed by a long-lasting induction of mTOR signaling, that was associated with an increased glycolytic capacity in MSC. When induced to switch their energetic metabolism towards glycolysis, MSC showed an improved ability to control T-cell proliferation. These results suggest that modifications of MSC energetic metabolism induced by IFNß may contribute to promote MSC immunomodulatory function and support a role for metabolic pathways in the therapeutic function of MSC. Altogether, these findings support the idea of a combined treatment for MS, in which the immunomodulatory and possibly regenerative activity of MSC could be enhanced by the administration of IFNß.


Assuntos
Glucose/metabolismo , Interferon beta/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Serina-Treonina Quinases TOR/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Glucose/imunologia , Imunomodulação/efeitos dos fármacos , Ativação Linfocitária , Células-Tronco Mesenquimais/metabolismo , Camundongos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Serina-Treonina Quinases TOR/metabolismo , Transfecção
13.
Cell Death Differ ; 26(2): 332-347, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29786074

RESUMO

Interferons (IFNs) are critical determinants in immune-competence and autoimmunity, and are endogenously regulated by a low-level constitutive feedback loop. However, little is known about the functions and origins of constitutive IFN. Recently, lipopolysaccharide (LPS)-induced IFN was implicated as a driver of necroptosis, a necrotic form of cell death downstream of receptor-interacting protein (RIP) kinase activation and executed by mixed lineage kinase like-domain (MLKL) protein. We found that the pre-established IFN status of the cell, instead of LPS-induced IFN, is critical for the early initiation of necroptosis in macrophages. This pre-established IFN signature stems from cytosolic DNA sensing via cGAS/STING, and maintains the expression of MLKL and one or more unknown effectors above a critical threshold to allow for MLKL oligomerization and cell death. Finally, we found that elevated IFN-signaling in systemic lupus erythematosus (SLE) augments necroptosis, providing a link between pathological IFN and tissue damage during autoimmunity.


Assuntos
Interferon beta/metabolismo , Macrófagos/metabolismo , Necroptose , Proteínas Quinases/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citosol/metabolismo , DNA/metabolismo , Técnicas de Inativação de Genes , Humanos , Interferon beta/genética , Interferon beta/farmacologia , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nucleotidiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
14.
Cancer Lett ; 440-441: 202-210, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30393160

RESUMO

Although mesenchymal stem cells (MSCs) have been reported to inhibit tumor growth, the mechanism controlling this tumor suppression function is unclear. Here, we report that high-density (40,000 cells/cm2) cultured adipose tissue-derived MSCs (40K-ASCs) expressed interferon (IFN)-ß and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); we also found that serum deprivation during cell culture induced the expression of IFN-ß and TRAIL. In addition, the mRNA expression of IFN-ß, but not TRAIL, was increased during the washing step required for the transplantation of normal-density (5000 cells/cm2) cultured ASCs (5K-ASCs). When the human lung cancer cell line H460 was co-cultured with 40K-ASCs, necrotic cell death was dramatically increased in vitro. When ASCs were injected after four washes, both 5K-ASCs and 40K-ASCs substantially reduced tumor weight in H460-derived cancer animal models. These results suggest that serum deprivation during the culture of 40K-ASCs or during the washing step of 5K-ASCs can induce IFN-ß and/or TRAIL expression, ultimately leading to the tumor suppression capability of ASCs.


Assuntos
Interferon beta/biossíntese , Neoplasias Pulmonares/terapia , Células-Tronco Mesenquimais/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/biossíntese , Adulto , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Interferon beta/genética , Interferon beta/farmacologia , Neoplasias Pulmonares/patologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Nus , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Adulto Jovem
15.
Mult Scler ; 25(3): 399-407, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29363396

RESUMO

BACKGROUND: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs). OBJECTIVES: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents. METHODS: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution. RESULTS: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis. CONCLUSION: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.


Assuntos
Progressão da Doença , Fatores Imunológicos/farmacologia , Esclerose Múltipla/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Fatores Etários , Criança , Feminino , Seguimentos , Acetato de Glatiramer/farmacologia , Humanos , Fatores Imunológicos/administração & dosagem , Injeções , Interferon beta/farmacologia , Itália , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
16.
Cell Mol Immunol ; 16(2): 178-194, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29553138

RESUMO

More than 40% of HIV infections occur via female reproductive tract (FRT) through heterosexual transmission. Epithelial cells that line the female genital mucosa are the first line of defense against HIV-1 and other sexually transmitted pathogens. These sentient cells recognize and respond to external stimuli by induction of a range of carefully balanced innate immune responses. Previously, we have shown that in response to HIV-1 gp120, the genital epithelial cells (GECs) from upper reproductive tract induce an inflammatory response that may facilitate HIV-1 translocation and infection. In this study, we report that the endometrial and endocervical GECs simultaneously induce biologically active interferon-ß (IFNß) antiviral responses following exposure to HIV-1 that act to protect the epithelial tight junction barrier. The innate antiviral response was directly induced by HIV-1 envelope glycoprotein gp120 and addition of gp120 neutralizing antibody inhibited IFNß production. Interferon-ß was induced by gp120 in upper GECs through Toll-like receptor 2 signaling and required presence of heparan sulfate on epithelial cell surface. The induction of IFNß was dependent upon activation of transcription factor IRF3 (interferon regulatory factor 3). The IFNß was biologically active, had a protective effect on epithelial tight junction barrier and was able to inhibit HIV-1 infection in TZM-bl indicator cells and HIV-1 replication in T cells. This is the first report that recognition of HIV-1 by upper GECs leads to induction of innate antiviral pathways. This could explain the overall low infectivity of HIV-1 in the FRT and could be exploited for HIV-1 prophylaxis.


Assuntos
Genitália Feminina/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Interferon beta/farmacologia , Membrana Mucosa/imunologia , Receptor 2 Toll-Like/imunologia , Adulto , Antivirais/farmacologia , Células Cultivadas , Endométrio/efeitos dos fármacos , Endométrio/imunologia , Endométrio/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Genitália Feminina/efeitos dos fármacos , Genitália Feminina/metabolismo , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imunidade Inata , Pessoa de Meia-Idade , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Receptor 2 Toll-Like/metabolismo
17.
Clin Immunol ; 200: 1-9, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30576845

RESUMO

Memory B cells are increased in systemic lupus erythematosus (SLE) cases, but the qualitative abnormalities and induction mechanism of these cells are unclear. Here, we subclassified B cells by their chemokine receptor expression and investigated their induction mechanism. The peripheral blood of patients with SLE showed higher levels of CXCR5- and CXCR3+ B cells. CXCR5-CXCR3+ B cell levels were elevated in patients with active SLE, which decreased with improving disease conditions. Interferon (IFN)-γ stimulation increased CXCR3 expression, whereas IFN-ß stimulation reduced CXCR5 expression in B cells. Furthermore, CXCR5-CXCR3+ B cells were induced by a combination of IFN-ß and IFN-γ stimulation. Renal tissue examination of patients with active lupus nephritis confirmed the presence of CD19+CXCR3+ B cells. Collectively, the results revealed qualitative abnormalities accompanying reduced CXCR5 expression via type I IFN and enhanced CXCR3 expression via type II IFN in SLE, suggesting their involvement in B cell infiltration into tissues and inflammatory pathogenesis.


Assuntos
Linfócitos B/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR5/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD19/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Memória Imunológica/imunologia , Interferon beta/imunologia , Interferon beta/farmacologia , Interferon gama/imunologia , Interferon gama/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores de Quimiocinas/metabolismo , Índice de Gravidade de Doença , Adulto Jovem
18.
Biomolecules ; 8(4)2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30274232

RESUMO

Nanoparticles can be used as a smart drug delivery system, when they release the drug only upon degradation by specific enzymes. A method to create such responsive materials is the formation of hydrogel nanoparticles, which have enzymatically degradable crosslinkers. Such hydrogel nanoparticles were prepared by ionotropic gelation sodium alginate with lysine-rich peptide sequences-either α-poly-L-lysine (PLL) or the aggrecanase-labile sequence KKKK-GRD-ARGSV↓NITEGE-DRG-KKKK. The nanoparticle suspensions obtained were analyzed by means of dynamic light scattering and nanoparticle tracking analysis. Degradation experiments carried out with the nanoparticles in suspension revealed enzyme-induced lability. Drugs present in the polymer solution during the ionotropic gelation can be encapsulated in the nanoparticles. Drug loading was investigated for interferon-ß (IFN-ß) as a model, using a bioluminescence assay with MX2Luc2 cells. The encapsulation efficiency for IFN-ß was found to be approximately 25%. The nanoparticles suspension can be used to spray-coat titanium alloys (Ti-6Al-4V) as a common implant material. The coatings were proven by ellipsometry, reflection-absorption infrared spectroscopy, and X-ray photoelectron spectroscopy. An enzyme-responsive decrease in layer thickness is observed due to the degradation of the coatings. The Alg/peptide coatings were cytocompatible for human gingival fibroblasts (HGFIB), which was investigated by CellTiterBlue and lactate dehydrogenase (LDH) assay. However, HGFIBs showed poor adhesion and proliferation on the Alg/peptide coatings, but these could be improved by modification of the alginate with a RGD-peptide sequence. The smart drug release system presented can be further tailored to have the right release kinetics and cell adhesion properties.


Assuntos
Biopolímeros/farmacologia , Materiais Revestidos Biocompatíveis/uso terapêutico , Liberação Controlada de Fármacos , Interferon beta/farmacologia , Biopolímeros/química , Quitosana/química , Quitosana/farmacologia , Materiais Revestidos Biocompatíveis/química , Fibroblastos/efeitos dos fármacos , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Hidrogel de Polietilenoglicol-Dimetacrilato/farmacologia , Interferon beta/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Polilisina/química , Polilisina/farmacologia , Propriedades de Superfície , Titânio/química
19.
Viruses ; 10(10)2018 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-30282907

RESUMO

Rubella virus (RV) infection impacts cellular metabolic activity in a complex manner with strain-specific nutritional requirements. Here we addressed whether this differential metabolic influence was associated with differences in oxidative stress induction and subsequently with innate immune response activation. The low passaged clinical isolates of RV examined in this study induced oxidative stress as validated through generation of the reactive oxygen species (ROS) cytoplasmic hydrogen peroxide and mitochondrial superoxide. The addition of the cytoplasmic and mitochondrial ROS scavengers N-acetyl-l-cysteine and MitoTEMPO, respectively, reduced RV-associated cytopathogenicity and caspase activation. While the degree of oxidative stress induction varied among RV clinical isolates, the level of innate immune response and interferon-stimulated gene activation was comparable. The type III IFNs were highly upregulated in all cell culture systems tested. However, only pre-stimulation with IFN ß slightly reduced RV replication indicating that RV appears to have evolved the ability to counteract innate immune response mechanisms. Through the data presented, we showed that the ability of RV to induce oxidative stress was independent of its capacity to stimulate and counteract the intrinsic innate immune response.


Assuntos
Interferons/metabolismo , Estresse Oxidativo , Vírus da Rubéola/isolamento & purificação , Vírus da Rubéola/metabolismo , Rubéola (Sarampo Alemão)/imunologia , Rubéola (Sarampo Alemão)/metabolismo , Acetilcisteína/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Humanos , Peróxido de Hidrogênio/metabolismo , Imunidade Inata , Interferon beta/metabolismo , Interferon beta/farmacologia , Interferons/farmacologia , Macrófagos/metabolismo , Macrófagos/virologia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
20.
Mult Scler Relat Disord ; 26: 33-36, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30216756

RESUMO

Interferon beta therapies have been effective in the treatment of relapsing forms of multiple sclerosis for over 2 decades. These therapies have varying routes and schedules of administration but broadly similar clinical and radiologic efficacy. The most commonly reported adverse effects are flu-like symptoms and injection site reactions. The most recent addition to the class is peginterferon beta-1a, which is administered subcutaneously every 2 weeks. Although clinically stable patients with multiple sclerosis may switch between platform therapies (such as interferons) based on tolerability or personal preference, few studies have explored the outcomes of switching. Herein I present 3 cases of patients who either initiated therapy with peginterferon beta-1a or switched from another interferon and had positive outcomes. With appropriate patient education and expectation setting regarding potential flu-like symptoms and injection-site reactions, peginterferon beta-1a may be a beneficial alternative for patients who prefer less frequent injections.


Assuntos
Fatores Imunológicos/farmacologia , Interferon beta-1a/farmacologia , Interferon beta/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Polietilenoglicóis/farmacologia , Adulto , Idoso , Substituição de Medicamentos , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Interferon beta-1a/administração & dosagem , Interferon beta/administração & dosagem , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem
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