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1.
Bull Exp Biol Med ; 171(6): 736-740, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34705177

RESUMO

We studied the effect of tilorone on the dynamics of IFNα, IFNγ, and IL-1ß levels in the lung tissue and blood serum in relation to viral load in the lungs of BALB/c mice with pneumonia caused by influenza virus A/Aichi/2/68 (H3N2). Tilorone was administered per os in doses of 40, 150, and 540 µg per mouse 6, 30, and 78 h postinfection, which simulated the drug regimen used in the clinic for the treatment of influenza and acute respiratory viral infections in Russia and post-Soviet countries. Tilorone reduced viral load with the maximum amplitude (2-3 lg) after 1-2 administrations. The results of studying the dynamics of the cytokine levels in the infected animals in general support the previous hypothesis that, in repeated dosing, tilorone enhances the IFN response (compensates for its deficiency) at the early stages of acute respiratory viral infections and suppresses (damps) excessive production of IFN and proinflammatory cytokines at the later stages.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Indutores de Interferon/farmacologia , Pulmão/efeitos dos fármacos , Infecções por Orthomyxoviridae/tratamento farmacológico , Tilorona/farmacologia , Animais , Esquema de Medicação , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Vírus da Influenza A Subtipo H3N2/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H3N2/patogenicidade , Interferon-alfa/sangue , Interferon-alfa/imunologia , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/sangue , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Carga Viral/efeitos dos fármacos
2.
Mol Immunol ; 136: 110-117, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34098343

RESUMO

Reticuloendothelial virus (REV) is widely found in many domestic poultry areas and results in severe immunosuppression of infected chickens. This increases the susceptibility to other pathogens, which causes economic losses to the poultry industry. The aim of our study was to determine whether polyinosinic-polycytidylic acid [Poly (I: C)] treatment could inhibit REV replication in chicken macrophage-like cell line, HD11. We found that Poly (I: C) treatment could markedly inhibit REV replication in HD11 from 24 to 48 h post infection (hpi). Additionally, Poly (I: C) treatment could switch HD11 from an inactive type into M1-like polarization from 24 to 48 hpi. Furthermore, Poly (I: C) treatment promoted interferon-ß secretion from HD11 post REV infection. Moreover, Toll-like receptor-3 (TLR-3) mRNA and protein levels in HD11 treated with Poly (I: C) were markedly increased compared to those of HD11 not treated with Poly (I: C). The above results suggested that Poly (I: C) treatment switches HD11 into M1-like polarization to secret more interferon-ß and activate TLR-3 signaling, which contributes to block REV replication. Our findings provide a theoretical reference for further studying the underlying pathogenic mechanism of REV and Poly (I: C) as a potential therapeutic intervention against REV infection.


Assuntos
Antivirais/farmacologia , Indutores de Interferon/farmacologia , Poli I-C/farmacologia , Vírus da Reticuloendoteliose Aviária/crescimento & desenvolvimento , Receptor 3 Toll-Like/metabolismo , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Galinhas , Interferon beta/biossíntese , Interferon beta/metabolismo , Macrófagos/imunologia , Macrófagos/virologia , Vírus da Reticuloendoteliose Aviária/efeitos dos fármacos , Infecções por Retroviridae/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Infecções Tumorais por Vírus/tratamento farmacológico
3.
J Neuroimmunol ; 357: 577620, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34062352

RESUMO

Neuropsychiatric systemic lupus erythematosus (NPSLE) is the most serious and complicated clinical manifestation of lupus erythematosus. Cognitive dysfunction is the most common symptom of NPSLE. A variety of potential mechanisms or mediators related to the pathogenesis of NPSLE cognitive dysfunction have been proposed. However, the involvement of microglia CD40 has not been reported yet. This study aimed to investigate whether hippocampal microglia CD40 of MRL/MpJ-Faslpr (MRL/lpr) mice was involved in NPSLE cognitive dysfunction. This study found, using quantitative polymerase chain reaction, western blotting and immunohistochemistry, that hippocampal CD40 was aberrantly overexpressed in the MRL/lpr lupus mice. It also determined using flow cytometry and immunofluorescence that the aberrantly overexpressed CD40 was mainly derived from hippocampal microglia. The adeno-associated virus was used to inhibit microglia CD40 expression, and the brain damage and cognitive dysfunction of MRL/lpr mice improved. Also, imiquimod (IMQ)-induced lupus mice had the same NPSLE cognitive dysfunction, brain damage, and overexpressed hippocampal microglia CD40 as MRL/lpr mice. Therefore, IMQ-induced lupus mouse was proposed as one of the mouse models for studying NPSLE cognitive dysfunction for the first time in this study. The findings indicated that hippocampal microglia CD40 was involved in the development of NPSLE cognitive dysfunction, thus providing a novel research direction for the study of the pathogenesis of NPSLE.


Assuntos
Antígenos CD40/metabolismo , Disfunção Cognitiva/metabolismo , Hipocampo/metabolismo , Vasculite Associada ao Lúpus do Sistema Nervoso Central/metabolismo , Microglia/metabolismo , Animais , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Feminino , Imiquimode/farmacologia , Indutores de Interferon/farmacologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Camundongos , Camundongos Endogâmicos MRL lpr
4.
J Leukoc Biol ; 110(6): 1197-1208, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33988261

RESUMO

Macrophage phagocytosis plays essential roles in antitumor immunity. CD47/SIRPα phagocytosis checkpoint blockade has demonstrated therapeutic potential in several hematopoietic cancers, but recent clinical studies reported very limited efficacy against solid malignancies. Here, we show that polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of double-stranded RNA, enhances the antitumor activity of CD47 blockade in colorectal cancer in vitro and in vivo. Poly(I:C) activation leads to a potent immune response characterized by the production of proinflammatory cytokines, especially IL-6. Stimulation with IL-6 promotes the PI3K signaling and cytoskeletal reorganization required for macrophage phagocytosis mediated by CD47 blockade. Our findings demonstrate the potential of Poly(I:C) to synergize the efficacy of CD47 blockade therapy and a novel role for IL-6 in macrophage phagocytosis, which provide new strategy for combinational cancer immunotherapy.


Assuntos
Neoplasias Colorretais/imunologia , Imunoterapia/métodos , Interleucina-6/biossíntese , Macrófagos/imunologia , Poli I-C/farmacologia , Animais , Antígeno CD47/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/imunologia , Indutores de Interferon/farmacologia , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia
5.
Cancer Res ; 81(12): 3374-3386, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33837043

RESUMO

Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17ß-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells in vitro and in vivo in a death ligand-dependent manner. Biochemical mechanism-of-action studies established bromo and extraterminal domain (BET) proteins as major cellular targets of PCC. Thus, by targeting of BET proteins to reduce antiapoptotic proteins and enhance caspase-8-dependent apoptosis of cancer cells, PCC represents a unique agent that can potentially be used in combination with various immunotherapeutic approaches to promote tumor regression and improve outcome. SIGNIFICANCE: These findings demonstrate that PCC selectively sensitizes cancer cells to immune-mediated cell death, potentially improving the efficacy of cancer immunotherapies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/12/3374/F1.large.jpg.


Assuntos
Produtos Biológicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Imunoterapia/métodos , Melanoma Experimental/tratamento farmacológico , Poli I-C/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Vitanolídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proliferação de Células , Quimioterapia Combinada , Feminino , Humanos , Indutores de Interferon/farmacologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
JCI Insight ; 6(8)2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33884963

RESUMO

It remains unresolved how retinal pigment epithelial cell metabolism is regulated following immune activation to maintain retinal homeostasis and retinal function. We exposed retinal pigment epithelium (RPE) to several stress signals, particularly Toll-like receptor stimulation, and uncovered an ability of RPE to adapt their metabolic preference on aerobic glycolysis or oxidative glucose metabolism in response to different immune stimuli. We have identified interleukin-33 (IL-33) as a key metabolic checkpoint that antagonizes the Warburg effect to ensure the functional stability of the RPE. The identification of IL-33 as a key regulator of mitochondrial metabolism suggests roles for the cytokine that go beyond its extracellular "alarmin" activities. IL-33 exerts control over mitochondrial respiration in RPE by facilitating oxidative pyruvate catabolism. We have also revealed that in the absence of IL-33, mitochondrial function declined and resultant bioenergetic switching was aligned with altered mitochondrial morphology. Our data not only shed new light on the molecular pathway of activation of mitochondrial respiration in RPE in response to immune stressors but also uncover a potentially novel role of nuclear intrinsic IL-33 as a metabolic checkpoint regulator.


Assuntos
Respiração Celular/fisiologia , Glicólise/fisiologia , Interleucina-33/metabolismo , Mitocôndrias/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Metabolismo Energético , Técnicas de Silenciamento de Genes , Glicólise/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Indutores de Interferon/farmacologia , Interleucina-33/efeitos dos fármacos , Interleucina-33/genética , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Oxidantes/farmacologia , Oxirredução/efeitos dos fármacos , Estresse Oxidativo , Poli I-C/farmacologia , Cultura Primária de Células , Ácido Pirúvico/metabolismo
7.
Methods Mol Biol ; 2239: 153-162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33226618

RESUMO

The discovery of induced pluripotent stem cells (iPSCs) allows for establishment of human embryonic stem-like cells from various adult human somatic cells (e.g., fibroblasts), without the need for destruction of human embryos. This provides an unprecedented opportunity where patient-specific iPSCs can be subsequently differentiated to many cell types, e.g., cardiac cells and neurons, so that we can use these iPSC-derived cells to study patient-specific disease mechanisms and conduct drug testing and screening. Critically, these cells have unlimited therapeutic potentials, and there are many ongoing clinical trials to investigate the regenerative potentials of these iPSC-derivatives in humans. However, the traditional iPSC reprogramming methods have problem of insertional mutagenesis because of use of the integrating viral vectors. While a number of advances have been made to mitigate this issue, including the use of chemicals, excisable and non-integrating vectors, and use of the modified mRNA, safety remains a concern. Both integrating and non-integrating methods also suffer from many other limitations including low efficiency, variability, and tumorigenicity. The non-integrating mRNA reprogramming is of high efficiency, but it is sensitive to reagents and need approaches to reduce the immunogenic reaction. An alternative non-integrating and safer way of generating iPSCs is via direct delivery of recombinant cell-penetrating reprogramming proteins into the cells to be reprogrammed, but reprogramming efficiency of the protein-based approach is extremely low compared to the conventional virus-based nuclear reprogramming. Herein, we describe detailed steps for efficient generation of human iPSCs by protein-based reprogramming in combination with stimulation of the Toll-like receptor 3 (TLR3) innate immune pathway.


Assuntos
Reprogramação Celular/genética , Células-Tronco Pluripotentes Induzidas/citologia , Poli I-C/farmacologia , Proteínas Recombinantes/metabolismo , Receptor 3 Toll-Like/metabolismo , Técnicas de Cultura de Células/métodos , Permeabilidade da Membrana Celular , Células Cultivadas , Criopreservação , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Indutores de Interferon/farmacologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Recombinantes/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transdução de Sinais/genética , Receptor 3 Toll-Like/genética
8.
Bioorg Med Chem Lett ; 30(24): 127613, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33075488

RESUMO

Type I Interferon (IFN) signaling plays an important role in the immune defense system against virus infection and in the innate immune response, thus IFNs are widely used as anti-viral agents and treatment for immune disorder or cancer. However, there is a growing demand for novel small-molecule IFN inducer due to tolerance, toxicity, or short duration of action following direct administration of IFNs. In this study, we assessed arylpiperazine (ARP) as a new core skeleton of IFN inducer. To investigate structure-activity relationship, we designed and synthesized a series of ARP analogues and evaluated the ability to stimulate IFN response in THP-1 human monocyte cells. Compound 5i was identified as a potent type I IFN inducer as it significantly increased cytokine secretion and increased expression of various IFN-stimulating genes which are representative biomarkers of type I IFN pathway. Our results suggested a beneficial therapeutic potential of 5i as an anti-viral agent.


Assuntos
Indutores de Interferon/química , Indutores de Interferon/farmacologia , Monócitos/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Desenho de Fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Indutores de Interferon/síntese química , Interferon Tipo I/agonistas , Interferon Tipo I/imunologia , Monócitos/imunologia , Piperazinas/síntese química , Células THP-1
9.
Alcohol Clin Exp Res ; 44(9): 1760-1768, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640038

RESUMO

BACKGROUND: The inbred mouse strain C57BL/6 is widely used in both models of addiction and immunological disease. However, there are pronounced phenotypic differences in ethanol (EtOH) consumption and innate immune response between C57BL/6 substrains. The focus of this study was to examine the effects of substrain on innate immune response and neuroimmune-induced escalation of voluntary EtOH consumption. The main goal was to identify whether substrain differences in immune response can account for differences in EtOH behavior. METHODS: We compared acute innate immune response with a viral dsRNA mimic, polyinosinic:polycytidylic acid (poly(I:C)), in brain using qRT-PCR in both C57BL/6N and C57BL/6J mice. Next, we used a neuroimmune model of escalation using poly(I:C) to compare drinking behavior between substrains. Finally, we compared brain neuroimmune response with both EtOH and repeated poly(I:C) in both substrains as a way to account for differences in EtOH behavior. RESULTS: We found that C57BL/6 substrains have differing immune response and drinking behaviors. C57BL/6N mice have a shorter but more robust inflammatory response to acute poly(I:C). In contrast, C57BL/6J mice have a smaller but longer-lasting acute immune response to poly(I:C). In our neuroimmune-induced escalation model, C57BL/6J mice but not C57BL/6N mice escalate EtOH intake after poly(I:C). Finally, only C57BL/6J mice show enhanced proinflammatory transcript abundance after poly(I:C) and EtOH, suggesting that longer-lasting immune responses are critical to neuroimmune drinking phenotypes. CONCLUSIONS: Altogether, this work has elucidated additional influences that substrain has on both innate immune response and drinking phenotypes. Our observations highlight the importance of considering and reporting the source and background used for production of transgenic and knockout mice. These data provide further evidence that genetic background must be carefully considered when investigating the role of neuroimmune signaling in EtOH abuse.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Comportamento Animal , Imunidade Inata/genética , Neuroimunomodulação/genética , Consumo de Bebidas Alcoólicas/imunologia , Consumo de Bebidas Alcoólicas/fisiopatologia , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Imunidade Inata/imunologia , Indutores de Interferon/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Modelos Animais , Neuroimunomodulação/imunologia , Poli I-C/farmacologia
10.
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 , COVID-19 , Células CACO-2 , Linhagem Celular Tumoral , Infecções por Coronavirus/tratamento farmacológico , Células Epiteliais/virologia , Humanos , Imunidade Inata , Pulmão/imunologia , Pandemias , Vírus da SARS/imunologia , SARS-CoV-2
11.
Proc Natl Acad Sci U S A ; 117(11): 5761-5771, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32132203

RESUMO

The circadian clock coordinates a variety of immune responses with signals from the external environment to promote survival. We investigated the potential reciprocal relationship between the circadian clock and skin inflammation. We treated mice topically with the Toll-like receptor 7 (TLR7) agonist imiquimod (IMQ) to activate IFN-sensitive gene (ISG) pathways and induce psoriasiform inflammation. IMQ transiently altered core clock gene expression, an effect mirrored in human patient psoriatic lesions. In mouse skin 1 d after IMQ treatment, ISGs, including the key ISG transcription factor IFN regulatory factor 7 (Irf7), were more highly induced after treatment during the day than the night. Nuclear localization of phosphorylated-IRF7 was most prominently time-of-day dependent in epidermal leukocytes, suggesting that these cell types play an important role in the diurnal ISG response to IMQ. Mice lacking Bmal1 systemically had exacerbated and arrhythmic ISG/Irf7 expression after IMQ. Furthermore, daytime-restricted feeding, which affects the phase of the skin circadian clock, reverses the diurnal rhythm of IMQ-induced ISG expression in the skin. These results suggest a role for the circadian clock, driven by BMAL1, as a negative regulator of the ISG response, and highlight the finding that feeding time can modulate the skin immune response. Since the IFN response is essential for the antiviral and antitumor effects of TLR activation, these findings are consistent with the time-of-day-dependent variability in the ability to fight microbial pathogens and tumor initiation and offer support for the use of chronotherapy for their treatment.


Assuntos
Ritmo Circadiano , Imunidade Inata/genética , Interferons/genética , Glicoproteínas de Membrana/genética , Pele/metabolismo , Receptor 7 Toll-Like/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Imiquimode/farmacologia , Indutores de Interferon/farmacologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/metabolismo , Interferons/metabolismo , Masculino , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pele/efeitos dos fármacos , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo
12.
Proc Natl Acad Sci U S A ; 117(10): 5409-5419, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094169

RESUMO

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.


Assuntos
Interferons/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Animais , Linfócitos B/imunologia , Linhagem Celular , Deleção de Genes , Humanos , Imiquimode/farmacologia , Inflamação/imunologia , Inflamação/patologia , Indutores de Interferon/farmacologia , Interferon Tipo I/fisiologia , Interferons/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/patologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/imunologia , Células Mesangiais/patologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Interferon/genética , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/fisiologia
13.
Colloids Surf B Biointerfaces ; 182: 110352, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306831

RESUMO

Psoriasis is a severe disfiguring skin disease affecting approximately 3% of people worldwide and negatively affecting their daily lives. The pathogenesis of psoriasis is complicated, and typical therapeutic strategies for psoriasis mainly focus on anti-inflammation. Considering the side effects, withdrawal rebound, high cost, and many other disadvantages of existing treatments, we developed a new topical therapeutic formulation consisting of niosomes loaded with celastrol, a triterpenoid extracted from Tripterygium. Celastrol niosomes were prepared by the thin film hydration method and probe sonication. The niosomes were composed of Span 20, Span 60, and cholesterol at a weight ratio of 3:1:1. The particle size of the niosomes was approximately 147 nm, with yield of up to 90%. Celastrol niosomes showed improved in vitro permeation ability compared to the raw drug. In our in vivo study, celastrol niosomes effectively alleviated erythema and scaling on the dorsal skin of psoriasis mouse models. Spleen weight and the levels of cytokines, including IL-22, IL-23, and IL-17, decreased after the treatment, indicating the high therapeutic potential of this formulation for psoriasis. In conclusion, encapsulation of celastrol by niosomes increased the water-solubility and permeation of celastrol into the skin, significantly improving its anti-psoriasis activity in mice.


Assuntos
Anti-Inflamatórios/farmacologia , Lipossomos/química , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Tripterygium/química , Triterpenos/farmacologia , Administração Cutânea , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/metabolismo , Biomarcadores/metabolismo , Colesterol/química , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Hexoses/química , Imiquimode/farmacologia , Indutores de Interferon/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Interleucinas/metabolismo , Lipossomos/administração & dosagem , Lipossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Triterpenos Pentacíclicos , Extratos Vegetais/química , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Pele/imunologia , Pele/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Triterpenos/isolamento & purificação , Triterpenos/metabolismo
14.
Dev Comp Immunol ; 100: 103423, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31254564

RESUMO

Rainbow trout (Oncorhynchus mykiss) face low environmental temperatures over winter months and during extreme low temperature events. Suboptimal temperatures are known to negatively impact the teleost immune system, although there is mixed evidence in rainbow trout as to the effect on the endogenous antigen processing and presentation pathway (EAPP). The EAPP is an important pathway for antiviral defense that involves the presentation of endogenous peptides on the cell surface for recognition by cytotoxic T cells. Using a rainbow trout hypodermal fibroblast (RTHDF) cell line as an in vitro model, we determined that constitutive EAPP transcript levels are not impaired at low temperature, but induction of up-regulation of these transcripts is delayed at the suboptimal temperature following exposure to poly(I:C) or viral haemorrhagic septicaemia virus IVb, which was still able to enter and replicate in the cell line at 4 °C, albeit with reduced efficiency. The delay in the induction of EAPP mRNA level up-regulation following poly(I:C) stimulation coincided with a delay in ifn1 transcript levels and secretion, which is important since interferon-stimulated response elements were identified in the promoter regions of the EAPP-specific members of the pathway, implying that IFN1 is involved in the regulation of these genes. Our results suggest that the ability of rainbow trout to mount an effective immune response to viral pathogens may be lessened at suboptimal temperatures.


Assuntos
Temperatura Baixa/efeitos adversos , Fibroblastos/imunologia , Doenças dos Peixes/imunologia , Proteínas de Peixes/metabolismo , Oncorhynchus mykiss/imunologia , Aclimatação/imunologia , Animais , Apresentação do Antígeno , Linhagem Celular , Fibroblastos/metabolismo , Doenças dos Peixes/virologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Indutores de Interferon/farmacologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Novirhabdovirus/imunologia , Oncorhynchus mykiss/virologia , Poli I-C/farmacologia , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
15.
J Immunol Res ; 2019: 1749803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31093508

RESUMO

Plasmacytoid dendritic cells (pDCs) express high levels of the toll-like receptors (TLRs) TLR7 and TLR9. In response to TLR7 and TLR9 ligands, pDCs are primary producers of type I interferons. Our previous study demonstrated that pDCs activated by the TLR7 ligand imiquimod (IMQ) and the TLR9 ligand CpG A can kill breast cancer cells in vitro and inhibit tumor growth in vivo. Moreover, we observed a distinctive morphological, phenotypic change in pDCs after activation by IMQ and CpG A. However, the effect of other TLR7 and TLR9 ligands on pDCs remains less understood. In this study, we treat pDCs with the TLR7 ligand IMQ, TLR7/8 ligands (CL097 and CL075), and three TLR9 ligands (different types of CpGs). The size of pDCs increased significantly after activation by TLR7, or TLR7/8 ligands. TLR7, TLR7/8, and TLR9 ligands similarly modulated cytokine release, as well as protein expression of pDC markers, costimulatory molecules, and cytotoxic molecules. Interestingly, TLR7/8 ligands, especially CL097, induced stronger responses. These results are relevant to the further study of the role and mechanism of pDC-induced antitumor effects and may aid in the development of a new strategy for future tumor immunotherapy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Imiquimode/farmacologia , Glicoproteínas de Membrana/imunologia , Oligodesoxirribonucleotídeos/farmacologia , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Animais , Feminino , Imidazóis/farmacologia , Indutores de Interferon/farmacologia , Interferon Tipo I/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/farmacologia , Tiazóis/farmacologia
16.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067687

RESUMO

Rhinovirus (RV) is the predominant virus causing respiratory tract infections. Bronchobini® is a low dose multi component, multi target preparation used to treat inflammatory respiratory diseases such as the common cold, described to ease severity of symptoms such as cough and viscous mucus production. The aim of the study was to assess the efficacy of Bronchobini® in RV infection and to elucidate its mode of action. Therefore, Bronchobini®'s ingredients (BRO) were assessed in an ex vivo model of RV infection using mouse precision-cut lung slices, an organotypic tissue capable to reflect the host immune response to RV infection. Cytokine profiles were assessed using enzyme-linked immunosorbent assay (ELISA) and mesoscale discovery (MSD). Gene expression analysis was performed using Affymetrix microarrays and ingenuity pathway analysis. BRO treatment resulted in the significant suppression of RV-induced antiviral and pro-inflammatory cytokine release. Transcriptome analysis revealed a multifactorial mode of action of BRO, with a strong inhibition of the RV-induced pro-inflammatory and antiviral host response mediated by nuclear factor kappa B (NFkB) and interferon signaling pathways. Interestingly, this was due to priming of these pathways in the absence of virus. Overall, BRO exerted its beneficial anti-inflammatory effect by priming the antiviral host response resulting in a reduced inflammatory response to RV infection, thereby balancing an otherwise excessive inflammatory response.


Assuntos
Antivirais/farmacologia , Indutores de Interferon/farmacologia , Interferons/metabolismo , Pulmão/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Extratos Vegetais/farmacologia , Transcriptoma , Animais , Antivirais/uso terapêutico , Feminino , Indutores de Interferon/uso terapêutico , Pulmão/metabolismo , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Picornaviridae/imunologia , Infecções por Picornaviridae/virologia , Extratos Vegetais/uso terapêutico , Rhinovirus/efeitos dos fármacos , Rhinovirus/patogenicidade , Transdução de Sinais
17.
eNeuro ; 6(2)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31016229

RESUMO

Sex differences are documented in psychiatric and neurological disorders, yet most preclinical animal research has been conducted in males only. There is a need to better understand of the nature of sex differences in brain disease in order to meet the needs of psychiatric patients. We present the behavior profile of adult female offspring produced using a maternal immune activation (MIA) model where pregnant rats receive an immune stimulant and the offspring typically show various abnormalities consistent with psychiatric illnesses such as schizophrenia and autism. The results in female offspring were compared to a previously published cohort of their male siblings (Lins et al., 2018). We examined prepulse inhibition (PPI), sociability, MK-801-induced locomotor activity, crossmodal object recognition (CMOR), and oddity discrimination; behaviors relevant to the positive, negative, and cognitive symptoms of schizophrenia. No between-treatment differences in PPI or locomotor activity were noted. Tactile memory was observed in the control and treated female offspring, visual recognition memory was deficient in the polyinosinic:polycytidylic acid (polyI:C) offspring only, and both groups lacked crossmodal recognition. PolyI:C offspring were impaired in oddity preference and had reduced preference for a stranger conspecific in a sociability assay. Systemic maternal CXCL1, IL-6, and TNF-a levels 3 h after polyI:C treatment were determined, but no relationship was found between these cytokines and the behavior seen in the adult female offspring. Overall, female offspring of polyI:C-treated dams display an array of behavior abnormalities relevant to psychiatric illnesses such as schizophrenia similar to those previously reported in male rats.


Assuntos
Comportamento Animal/fisiologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Inibição Pré-Pulso/fisiologia , Reconhecimento Psicológico/fisiologia , Comportamento Social , Animais , Modelos Animais de Doenças , Feminino , Indutores de Interferon/farmacologia , Poli I-C/farmacologia , Gravidez , Ratos , Ratos Sprague-Dawley , Esquizofrenia/fisiopatologia , Caracteres Sexuais
18.
Thorax ; 74(1): 43-50, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30076187

RESUMO

BACKGROUND: We previously reported that microvesicles (MVs) released by human mesenchymal stem cells (MSC) were as effective as the cells themselves in both Escherichia coli lipopolysaccharide and live bacteria-induced acute lung injury (ALI) mice models. However, it remained unclear whether the biological effect of MSC MV can be applied to human ALI. METHODS: In the current study, we tested the therapeutic effects of MSC MVs in a well-established ex vivo perfused human model of bacterial pneumonia. Using human donor lungs not used for transplantation, we instilled E. coli bacteria intrabronchially and, 1 hour later, administered MSC MVs into the perfusate as therapy. RESULTS: After 6 hours, instillation of E. coli bacteria caused influx of inflammatory cells, which resulted in significant inflammation, lung protein permeability and pulmonary oedema formation. Administration of MSC MV significantly increased alveolar fluid clearance and reduced protein permeability and numerically lowered the bacterial load in the injured alveolus. The beneficial effect on bacterial killing was more pronounced with pretreatment of MSCs with a Toll-like receptor 3 agonist, polyinosinic:polycytidylic acid (Poly (I:C)), prior to the isolation of MVs. Isolated human alveolar macrophages had increased antimicrobial activity with MSC MV treatment in vitro as well. Although oxygenation and lung compliance levels were similar between injury and treatment groups, administration of MSC MVs numerically decreased median pulmonary artery pressure at 6 hours. CONCLUSIONS: In summary, MSC MVs increased alveolar fluid clearance and reduced lung protein permeability, and pretreatment with Poly (I:C) enhanced the antimicrobial activity of MVs in an ex vivo perfused human lung with severe bacteria pneumonia.


Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Lesão Pulmonar Aguda/terapia , Terapia Baseada em Transplante de Células e Tecidos , Micropartículas Derivadas de Células , Infecções por Escherichia coli/complicações , Células-Tronco Mesenquimais , Pneumonia Bacteriana/complicações , Proteínas/metabolismo , Alvéolos Pulmonares/metabolismo , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/patologia , Adulto , Idoso , Pressão Arterial , Carga Bacteriana , Micropartículas Derivadas de Células/efeitos dos fármacos , Feminino , Humanos , Indutores de Interferon/farmacologia , Contagem de Leucócitos , Complacência Pulmonar , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Neutrófilos , Técnicas de Cultura de Órgãos , Oxigênio/metabolismo , Permeabilidade , Poli I-C/farmacologia , Alvéolos Pulmonares/microbiologia , Alvéolos Pulmonares/patologia , Artéria Pulmonar , Edema Pulmonar/microbiologia , Edema Pulmonar/terapia , Receptor 3 Toll-Like/agonistas , Fator de Necrose Tumoral alfa/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-30292753

RESUMO

Bcl6B, also known as BAZF, plays important roles in the immune response, repression of cancers, and maintenance of spermatogonial stem cells in mammals. In this study, the homologous gene bcl6b and its 5 alternative splicing variants, namely bcl6bX1 to bcl6bX5, were isolated from medaka fish, Oryzias latipes. Medaka bcl6b possesses conserved domains such as BTB domain, RD2 domain and four zinc fingers. Medaka bcl6bX1 to bcl6bX3 possess all three previously mentioned domains with minor differences in sequences. Medaka bcl6bX4 possesses only the BTB domain due to premature stopping, and bcl6bX5 possesses both the BTB domain and zinc fingers without the RD2 domain. Medaka bcl6b was expressed in the tissues including the brain, heart, gill, muscle, spleen, kidney, intestine, ovary and testes of adult fish. Medaka bcl6b was expressed in the embryos from very early stage, and could be detected clearly in the developing eyes by RT-PCR and in situ hybridization. Medaka bcl6b could respond to the stimuli of polyI:C and LPS in the kidney and spleen. Medaka bcl6bX1 to bcl6bX3 were the majority of the variants expressed in the adult tissues and the embryos, and were the major response to the stimulation of polyI:C and LPS in the spleen. These results suggested that bcl6b, including its isoforms, could function in various tissues and embryogenesis. Moreover, bcl6b might be a factor for immune response in medaka.


Assuntos
Processamento Alternativo , Desenvolvimento Embrionário , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Oryzias/fisiologia , Proteínas Repressoras/metabolismo , Processamento Alternativo/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sequência Conservada , Embrião não Mamífero/imunologia , Embrião não Mamífero/fisiologia , Olho/embriologia , Olho/metabolismo , Proteínas de Peixes/química , Proteínas de Peixes/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Indutores de Interferon/farmacologia , Rim/efeitos dos fármacos , Rim/crescimento & desenvolvimento , Rim/imunologia , Rim/metabolismo , Lipopolissacarídeos/farmacologia , Especificidade de Órgãos , Oryzias/embriologia , Oryzias/crescimento & desenvolvimento , Oryzias/imunologia , Poli I-C/farmacologia , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Distribuição Aleatória , Proteínas Repressoras/química , Proteínas Repressoras/genética , Alinhamento de Sequência , Baço/efeitos dos fármacos , Baço/crescimento & desenvolvimento , Baço/imunologia , Baço/metabolismo
20.
PLoS One ; 13(11): e0206827, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383838

RESUMO

Hyperuricaemia is associated with various metabolic dysfunctions including obesity, type 2 diabetes mellitus, hypertension and in general metabolic syndrome, which are all associated with increased risk of cancer. However, the direct association between elevated uricemia and cancer mortality still remains unclear. In this study, we used a mouse model of hyperuricemia, the Urahplt2/plt2 (PLT2) mouse, to investigate the effect of high uric acid levels on anti-tumor immune responses and tumor growth. In normo-uricaemic C57BL/6 mice injected with B16 melanomas, immunotherapy by treatment with Poly I:C at the tumor site delayed tumor growth compared to PBS treatment. In contrast, Poly I:C-treated hyper-uricaemic PLT2 mice were unable to delay tumor growth. Conventional and monocyte-derived dendritic cells in the tumor-draining lymph nodes (dLN) of C57BL/6 and PLT2 mice were similarly increased after Poly I:C immunotherapy, and expressed high levels of CD40 and CD86. CD8+ T cells in the tumor-dLN and tumor of both WT and PLT2 mice were also increased after Poly I:C immunotherapy, and were able to secrete increased IFNγ upon in vitro restimulation. Surprisingly, tumor-specific CD8+ T cells in dLN were less abundant in PLT2 mice compared to C57BL/6, but showed a greater ability to proliferate even in the absence of cognate antigen. These data suggest that hyperuricaemia may affect the functionality of CD8+ T cells in vivo, leading to dysregulated T cell proliferation and impaired anti-tumor activity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hiperuricemia/imunologia , Indutores de Interferon/farmacologia , Melanoma Experimental/imunologia , Poli I-C/farmacologia , Neoplasias Cutâneas/imunologia , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Carcinogênese/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/genética , Hiperuricemia/metabolismo , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunoterapia/métodos , Indutores de Interferon/uso terapêutico , Linfonodos/citologia , Linfonodos/imunologia , Masculino , Melanoma Experimental/sangue , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Poli I-C/uso terapêutico , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Resultado do Tratamento , Ácido Úrico/sangue , Ácido Úrico/metabolismo
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