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1.
Monoclon Antib Immunodiagn Immunother ; 38(6): 277-281, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31742481

RESUMO

Helicobacter pylori infection occurs throughout the world between countries and races. A seroprevalence study of H. pylori infection in the occurrence of atherosclerosis (ASc) has been considered to be the main cause of cardiovascular diseases (CVDs) in part of Iran. From 600 volunteers, 97 serum samples were selected and tested for the presence of H. pylori infection. Positive and negative H. pylori infection samples were then selected for Chlamydia pneumonia and cytomegalovirus infection. Their serum levels for high-sensitive C-reactive protein (hs-CRP) and IL-6 titer were measured using an ELISA test. Prevalence of H. pylori infection was ∼68.04% in Karaj. Among the 22 samples of cytokine titration, 4 individuals were HP- and 18 were HP+. It was also noticed that 17 samples had normal titration (77.27%) of IL-6 and 3 had a high level of IL-6 (13.63%), 20 people had high hs-CRP titration (90.90%), and 2 were low level hs-CRP (9.1%). Obtained results showed that there is no significant difference between HP+ and HP- infection and IL-6 and hs-CRP titration. Results showed that H. pylori could not lead to ASc by increasing the levels of proinflammatory cytokines such as IL-6 and hs-CRP. Further studies are necessary for the detection of mechanism of H. pylori on ASc.


Assuntos
Aterosclerose/sangue , Doenças Cardiovasculares/sangue , Infecções por Helicobacter/sangue , Helicobacter pylori/imunologia , Adolescente , Adulto , Idoso , Anticorpos Antibacterianos/sangue , Aterosclerose/epidemiologia , Aterosclerose/imunologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Criança , Feminino , Infecções por Helicobacter/epidemiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Humanos , Interleucina-3/imunologia , Interleucina-6/imunologia , Irã (Geográfico)/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto Jovem
2.
Medicine (Baltimore) ; 98(38): e17315, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568018

RESUMO

Early differential diagnosis of bloodstream infections (BSIs) caused by different sources and species of bacteria in hospitalized patients is crucial for the timely targeted interventions including appropriate use of antibiotics. The aim of this study was to identify 9 biomarkers for the early differentiation of gram-negative-bloodstream infection (GN-BSI), gram-positive (GP)-BSI, and fungal-BSI.A prospective study was conducted for a total of 390 inpatients who underwent blood culture in the Chinese PLA General Hospital from September 2015 to March 2018. Patients with positive culture of a single pathogen were divided into GN-BSI, GP-BSI, and Fungal-BSI groups, and a culture-negative disease control group was also established. The serum levels of macrophage inflammatory protein 1ß (MIP-1ß), tumor necrosis factor α (TNF-α), interleukin (IL)-3, interferon (IFN)-γ, IL-17A, IL-4, IL-12p70, and P-selectin were detected and the NLR was calculated from routine blood test. Receiver-operating characteristic analysis was used to determine the efficacy of various indicators in the differential diagnosis of BSIs. Prediction and validation experiments on clinical patient samples (263 cases) were also performed.The level of IL-3 in the GP-BSI group was significantly higher than those in the other 3 groups. The level of IFN-γ in the fungal-BSI group was significantly higher than those in the other 3 groups. NLR, MIP-1ß, TNF-α, IL-17A, and IL3 exhibited some efficacy when distinguishing between GN-BSI and GP-BSI and NLR had the largest area under curve (AUC) (0.728), followed by MIP-1ß with an AUC of 0.679. IFN-γ and IL-3 exhibited some value in differential diagnosis between GN-BSI and Fungal-BSI. IL-3, MIP-1ß, TNF-α, IFN-γ, NLR, IL-17A, and IL-4 exhibited some value in distinguishing fungal-BSI and GP-BSI, with IL-3 had the largest AUC (0.722), followed by MIP-1ß with an AUC of 0.703.NLR and MIP-1ß may be valuable in differentiating GN-BSI from GP-BSI in hospitalized patients. IFN-γ and IL-3 may be helpful in differential diagnosis GN-BSI and fungal-BSI. IL-3 and MIP-1ß exhibited some diagnostic efficacy in distinguishing fungal-BSI and GP-BSI. Additionally, IL-3 with high serum level may be a marker for GP-BSI and IFN-γ with high serum level may be a valuable marker for the prediction of Fungal-BSI. The utility of these biomarkers to predict BSIs owing to different pathogens in hospitalized patients needs to be assessed in further studies.


Assuntos
Bacteriemia/diagnóstico , Quimiocina CCL4/sangue , Infecção Hospitalar/diagnóstico , Infecções por Bactérias Gram-Negativas/diagnóstico , Infecções por Bactérias Gram-Positivas/diagnóstico , Interferon gama/sangue , Interleucina-12/sangue , Interleucina-17/sangue , Interleucina-3/sangue , Interleucina-4/sangue , Micoses/diagnóstico , Proteínas NLR/sangue , Selectina-P/sangue , Fator de Necrose Tumoral alfa/sangue , Bacteriemia/sangue , Bacteriemia/microbiologia , Biomarcadores/sangue , Infecção Hospitalar/sangue , Infecção Hospitalar/microbiologia , Diagnóstico Diferencial , Feminino , Infecções por Bactérias Gram-Negativas/sangue , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Positivas/sangue , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/sangue , Micoses/microbiologia , Estudos Prospectivos
3.
Infect Immun ; 87(12)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31591168

RESUMO

The physiopathology of malaria, one of the most deadly human parasitic diseases worldwide, is complex, as it is a systemic disease involving multiple parasitic stages and hosts and leads to the activation of numerous immune cells and release of inflammatory mediators. While some cytokines increased in the blood of patients infected with Plasmodium falciparum have been extensively studied, others, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), have not received much attention. GM-CSF and IL-3 belong to the ß common (ßc/CD131) chain family of cytokines, which exhibit pleiotropic functions, including the regulation of myeloid cell growth, differentiation, and activation. GM-CSF can be secreted by multiple cell types, whereas IL-3 is mostly restricted to T cells, yet innate response activator (IRA) B cells, a subset of innate B1 B cells, also produce significant amounts of these cytokines during bacterial sepsis via Toll-like receptor 4 (TLR4)/MyD88 sensing of lipopolysaccharides. Herein, using murine models of malaria, we report a sustained production of GM-CSF and IL-3 from IgM+ and IgM-/IgG+ CD138+ Blimp-1+ innate B1b B cell plasmablasts. IgM+ B1b B cells include IRA-like and non-IRA B cells and express higher levels of both cytokines than do their IgG+ counterparts. Interestingly, as infection progresses, the relative proportion of IgM+ B1 B cells decreases while that of IgG+ plasmablasts increases, correlating with potential isotype switching of GM-CSF- and IL-3-producing IgM+ B1 B cells. GM-CSF/IL-3+ B1 B cells originate in the spleen of infected mice and are partially dependent on type I and type II interferon signaling to produce both cytokines. These data reveal that GM-CSF and IL-3 are produced during malaria infections, initially from IgM+ and then from IgG+ B1b B cell plasmablasts, which may represent important emergency cellular sources of these cytokines. These results further highlight the phenotypic heterogeneity of innate B1 B cell subsets and of their possible fates in a relevant murine model of parasitic infection in vivo.


Assuntos
Subpopulações de Linfócitos B/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-3/metabolismo , Malária/imunologia , Plasmodium chabaudi/imunologia , Plasmodium yoelii/imunologia , Animais , Modelos Animais de Doenças , Ativação Linfocitária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Baço/imunologia
4.
BMC Pulm Med ; 19(1): 158, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438916

RESUMO

BACKGROUND: Severe non-allergic eosinophilic asthma (SNEA) is a rare asthma phenotype associated with severe clinical course, frequent exacerbations, and resistance to therapy, including high steroid doses. The key feature is type 2 inflammation with predominant airway eosinophilia. Eosinophil maturation, activation, survivability, and recruitment are mainly induced by interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) through their receptors on eosinophil surface and related with integrins activation states. The aim of the study was to estimate the expression of eosinophil ß chain-signaling cytokines receptors, outer-membrane integrins, and serum-derived type 2 inflammation biomarkers in SNEA. METHODS: We examined 8 stable SNEA patients with high inhaled steroid doses, 12 steroid-free patients with non-severe allergic asthma (AA), 12 healthy subjects (HS). Blood eosinophils were isolated using Ficol gradient centrifugation and magnetic separation. Eosinophils were lysed, and mRNA was isolated. Gene expressions of IL-5Rα, IL-3Rα, GM-CSFRα, and α4ß1, αMß2 integrins were analyzed using quantitative real-time reverse transcription polymerase chain reaction. Type 2 inflammation activity was evaluated measuring exhaled nitric oxide concentration (FeNO) collected with the electrochemical sensing device. Serum IL-5, IL-3, GM-CSF, periostin, chemokine ligand (CCL) 17 and eotaxin concentrations were assessed by enzyme-linked immunosorbent assay. RESULTS: Eosinophils from SNEA patients demonstrated significantly increased gene expression of IL-3Rα, IL-5Rα and GM-CSFRα as well as α4, ß1 and αM integrin subunits compared with the AA group. The highest IL-5 serum concentration was in the SNEA group; it significantly differed compared with AA and HS. GM-CSF serum levels were similar in the SNEA and AA groups and were significantly lower in the HS group. No differences in serum IL-3 concentration were found among all groups. Furthermore, serum levels of eotaxin, CCL17 and FeNO, but not periostin, differed in all groups, with the highest levels in SNEA patients. CONCLUSIONS: Eosinophil demonstrated higher expression of IL-3, IL-5, GM-CSF α-chain receptors and α4, ß1, αM integrins subunits in SNEA compared with the AA group. Additionally, SNEA patients had increased serum levels of IL-5, eotaxin and CCL-17. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03388359.


Assuntos
Asma/sangue , Eosinófilos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Integrinas/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Adulto , Asma/fisiopatologia , Biomarcadores/sangue , Quimiocina CCL17/sangue , Feminino , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Inflamação/metabolismo , Interleucina-3/sangue , Interleucina-3/genética , Interleucina-5/sangue , Interleucina-5/genética , Contagem de Leucócitos , Lituânia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Adulto Jovem
5.
Life Sci ; 232: 116663, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323275

RESUMO

AIMS: CD123 represents an important acute myeloid leukemia (AML) therapeutic target. CD123 aptamers may potentially serve as tumor-homing ligands with excellent affinity and specificity for AML targeted therapy, but their complexity, laborious preparation and nuclease digestion limited pharmacological application. The aim of this study was to develop the first CD123 thioaptamer to overcome these obstacles. MAIN METHODS: Flow cytometry was utilized to assess the binding specificity, affinity and anti-nuclease ability of thioaptamer. CCK8, Annexin-V/DAPI, and colony forming assays were used to evaluate the anti-cancer ability of thioaptamer in vitro. The tumor volume, weights, survival rate, H&E staining of organs, and serum level of organ damage biomarkers of animal model were applied to investigate the anti-cancer ability of thioaptamer in vivo. Furthermore, we explored the binding mechanism between thioaptamer and CD123. KEY FINDINGS: CD123 thioaptamer SS30 was able to bind to CD123 structure with high specificity in complex nuclease environment, the dissociation constant of 39.1 nM for CD123 peptide and 287.6 nM for CD123+ AML cells, while exhibiting minimal cross-reactivity to albumin. Furthermore, SS30 inhibited the proliferation and survival of AML cell lines and human AML blasts selectively in vitro (P < 0.01). In addition, SS30 prolonged the survival and inhibited tumor growth in a mouse xenograft tumor model in vivo. Of note, SS30 blocked the interaction between IL-3 and CD123, and decreased expression of p-STAT5 and p-AKT. SIGNIFICANCE: The proliferation inhibition and nuclease resistance ability of SS30 made it as a more promising functional molecule for AML targeted therapy.


Assuntos
Antineoplásicos/farmacologia , Aptâmeros de Peptídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-3/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Interleucina-3/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos
6.
Immunohorizons ; 3(5): 161-171, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31356170

RESUMO

During Ag priming, naive CD4+ T cells differentiate into subsets with distinct patterns of cytokine expression that dictate to a major extent their functional roles in immune responses. We identified a subset of CD4+ T cells defined by secretion of IL-3 that was induced by Ag stimulation under conditions different from those associated with previously defined functional subsets. Using mouse models of bacterial and viral infections, we showed that IL-3-secreting CD4+ T cells were generated by infection at the skin and mucosa but not by infections introduced directly into the blood. Most IL-3-producing T cells coexpressed GM-CSF and other cytokines that define multifunctionality. Generation of IL-3-secreting T cells in vitro was dependent on IL-1 family cytokines and was inhibited by cytokines that induce canonical Th1 or Th2 cells. Our results identify IL-3-secreting CD4+ T cells as a potential functional subset that arises during priming of naive T cells in specific tissue locations.


Assuntos
Interleucina-3/biossíntese , Membrana Mucosa/microbiologia , Pele/microbiologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Herpes Genital/virologia , Herpesvirus Humano 2/imunologia , Listeria monocytogenes/imunologia , Listeriose/microbiologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membrana Mucosa/imunologia , Membrana Mucosa/virologia , Mycobacterium bovis/imunologia , Pele/imunologia , Pele/virologia , Tuberculose/microbiologia
7.
Radiat Res ; 192(3): 267-281, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31295086

RESUMO

Serpins are a group of serine-proteases involved in multiple signal transduction pathways in mammalian cells. In particular, Serpinb3a is involved in the lysosomal necrosis cell death pathway with components that overlap with radiation-induced apoptosis. We investigated the radiation response of Serpinb3a-/- mice compared to Serpinb3a+/+ mice on the Balb/c background. Serpinb3a-/- mice showed significant radioresistance to a dose of 8.0 Gy total-body irradiation, compared to Serpinb3a+/+ Balb/c mice. Long-term bone marrow cultures from Serpinb3a-/- mice showed increased longevity. In clonogenic survival assays, fresh bone marrow hematopoietic progenitors, as well as clonal interleukin-3 (IL-3)-dependent hematopoietic progenitor and bone marrow stromal cell lines from Serpinb3a-/- mice were radioresistant. Serpinb3a-/- mouse bone marrow-derived stromal cell lines had increased baseline and postirradiation antioxidant capacity. Serpinb3a-/- bone marrow stromal cells showed increased radiation-induced RNA transcripts for MnSOD and p21, and decreased levels of p53 and TGF-b. Both irradiated Serpinb3a-/- mouse bone marrow stromal cell lines and plasma removed from total-body irradiated mice had decreased levels of expression of stress response and inflammation-associated proteins. Abrogation of Serpinb3a may be a potential new target for mitigation of radiation effects.


Assuntos
Células-Tronco Hematopoéticas/efeitos da radiação , Células-Tronco Mesenquimais/efeitos da radiação , Tolerância a Radiação , Serpinas/deficiência , Animais , Apoptose/efeitos da radiação , Linhagem Celular , Movimento Celular/efeitos da radiação , Deleção de Genes , Hematopoese/efeitos da radiação , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Interleucina-3/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Serpinas/genética
8.
J Immunol ; 203(2): 329-337, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31175163

RESUMO

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common ß subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the ß-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.


Assuntos
Citocinas/imunologia , Eosinófilos/imunologia , Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interleucina-3/imunologia , Interleucina-5/imunologia , Asma/imunologia , Regulação para Baixo/imunologia , Humanos , Transdução de Sinais/imunologia , Regulação para Cima/imunologia
9.
Int J Biol Macromol ; 136: 209-219, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31199972

RESUMO

Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, constitutively active somatic JAK2 mutations were important for the leukemogenesis of acute leukemia (AL). The JAK2 R867Q somatic mutation is detected in a subset of AL patients. However, roles of JAK2 R867Q mutation in the pathogenesis of AL remain unclear. In this study, homology modeling analysis showed that loss of interaction between R867 and Y613 disrupted the JAK2 JH1/JH2 domain's interactions was responsible for its activation. JAK2 R867Q and mutations (R867A and R867G) abolished this interaction caused JAK2 constitutive activation. While, mutations (R867K, Y613E, R867K/Y613E) repairing this interaction reduced JAK2 R867Q mutation's activity. Furthermore, our studies showed that abolished R867 and Y613 interaction disrupted JH1/JH2 domains' interactions and led to JAK2 constitutive activation. More importantly, mutations (R867Q, R867A and R867G) disrupted this interaction enhanced the activity of JAK2-STAT5 pathway and the proliferation of Ba/F3 and MV4-11 cells. Further study showed that JAK2 R867Q mutation promoted the expression of proliferation marker and inhibited the differentiation marker of Ba/F3 and MV4-11 cells. Thus our studies provide clues in understanding the pathogenesis of JAK2 R867Q mutation in AL.


Assuntos
Janus Quinase 2/química , Janus Quinase 2/metabolismo , Leucemia/genética , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Mutação , Doença Aguda , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Humanos , Interleucina-3/farmacologia , Janus Quinase 2/genética , Leucemia/patologia , Modelos Moleculares , Proteínas Mutantes/genética , Redobramento de Proteína , Estrutura Secundária de Proteína/genética , Estrutura Terciária de Proteína/genética
10.
Arterioscler Thromb Vasc Biol ; 39(7): 1275-1287, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31092009

RESUMO

Growth factors, such as CSFs (colony-stimulating factors), EGFs (epidermal growth factors), and FGFs (fibroblast growth factors), are signaling proteins that control a wide range of cellular functions. Although growth factor networks are critical for intercellular communication and tissue homeostasis, their abnormal production or regulation occurs in various pathologies. Clinical strategies that target growth factors or their receptors are used to treat a variety of conditions but have yet to be adopted for cardiovascular disease. In this review, we focus on M-CSF (macrophage-CSF), GM-CSF (granulocyte-M-CSF), IL (interleukin)-3, EGFR (epidermal growth factor receptor), and FGF21 (fibroblast growth factor 21). We first discuss the efficacy of targeting these growth factors in other disease contexts (ie, inflammatory/autoimmune diseases, cancer, or metabolic disorders) and then consider arguments for or against targeting them to treat cardiovascular disease. Visual Overview- An online visual overview is available for this article.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Humanos , Imunoterapia , Interleucina-3/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores
11.
Blood Adv ; 3(9): 1499-1511, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31076406

RESUMO

JMJD1C, a member of the lysine demethylase 3 family, is aberrantly expressed in mixed lineage leukemia (MLL) gene-rearranged (MLLr) leukemias. We have shown previously that JMJD1C is required for self-renewal of acute myeloid leukemia (AML) leukemia stem cells (LSCs) but not normal hematopoietic stem cells. However, the domains within JMJD1C that promote LSC self-renewal are unknown. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) negative-selection screening and identified a requirement for the catalytic Jumonji (JmjC) domain and zinc finger domain for leukemia cell survival in vitro and in vivo. In addition, we found that histone H3 lysine 36 methylation (H3K36me) is a marker for JMJD1C activity at gene loci. Moreover, we performed single cell transcriptome analysis of mouse leukemia cells harboring a single guide RNA (sgRNA) against the JmjC domain and identified increased activation of RAS/MAPK and the JAK-STAT pathway in cells harboring the JmjC sgRNA. We discovered that upregulation of interleukin 3 (IL-3) receptor genes mediates increased activation of IL-3 signaling upon JMJD1C loss or mutation. Along these lines, we observed resistance to JMJD1C loss in MLLr AML bearing activating RAS mutations, suggesting that RAS pathway activation confers resistance to JMJD1C loss. Overall, we discovered the functional importance of the JMJD1C JmjC domain in AML leukemogenesis and a novel interplay between JMJD1C and the IL-3 signaling pathway as a potential resistance mechanism to targeting JMJD1C catalytic activity.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Oxirredutases N-Desmetilantes/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Edição de Genes , Histonas/metabolismo , Humanos , Interleucina-3/metabolismo , Histona Desmetilases com o Domínio Jumonji/química , Histona Desmetilases com o Domínio Jumonji/genética , Leucemia Mieloide Aguda/genética , Camundongos , Camundongos Endogâmicos C57BL , Oxirredutases N-Desmetilantes/química , Oxirredutases N-Desmetilantes/genética , Domínios Proteicos , RNA Guia/metabolismo , Transdução de Sinais , Transplante Heterólogo , Dedos de Zinco/genética
12.
J Immunol ; 202(12): 3514-3523, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31068389

RESUMO

Chronic rejection is a major problem in transplantation medicine, largely resistant to therapy, and poorly understood. We have shown previously that basophil-derived IL-4 contributes to fibrosis and vasculopathy in a model of heart transplantation with depletion of CD4+ T cells. However, it is unknown how basophils are activated in the allografts and whether they play a role when cyclosporin A (CsA) immunosuppression is applied. BALB/c donor hearts were heterotopically transplanted into fully MHC-mismatched C57BL/6 recipients and acute rejection was prevented by depletion of CD4+ T cells or treatment with CsA. We found that IL-3 is significantly upregulated in chronically rejecting allografts and is the major activator of basophils in allografts. Using IL-3-deficient mice and depletion of basophils, we show that IL-3 contributes to allograft fibrosis and organ failure in a basophil-dependent manner. Also, in the model of chronic rejection involving CsA, IL-3 and basophils substantially contribute to organ remodeling, despite the almost complete suppression of IL-4 by CsA. In this study, basophil-derived IL-6 that is resistant to suppression by CsA, was largely responsible for allograft fibrosis and limited transplant survival. Our data show that IL-3 induces allograft fibrosis and chronic rejection of heart transplants, and exerts its profibrotic effects by activation of infiltrating basophils. Blockade of IL-3 or basophil-derived cytokines may provide new strategies to prevent or delay the development of chronic allograft rejection.


Assuntos
Basófilos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração , Interleucina-3/metabolismo , Animais , Movimento Celular , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Humanos , Interleucina-3/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante Homólogo , Regulação para Cima
13.
Immunity ; 50(4): 796-811, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995500

RESUMO

The ß common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the ß common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Inflamação/imunologia , Interleucina-3/imunologia , Interleucina-5/imunologia , Animais , Doenças Autoimunes/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hematopoese/imunologia , Humanos , Inflamação/terapia , Interleucina-3/antagonistas & inibidores , Interleucina-3/deficiência , Interleucina-3/genética , Interleucina-5/antagonistas & inibidores , Interleucina-5/deficiência , Interleucina-5/genética , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais , Relação Estrutura-Atividade , Vacinação , Cicatrização/imunologia
14.
Ann N Y Acad Sci ; 1445(1): 62-73, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30945313

RESUMO

One successful class of cancer immunotherapies, immune checkpoint inhibitory antibodies, disrupts key pathways that regulate immune checkpoints, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). These agents unleash the potency of antigen-experienced T cells that have already been induced as a consequence of the existing tumor. But only 20% of cancers naturally induce T cells. For most cancers, vaccines are require to induce and mobilize T effector cells (Teffs ) to traffick into tumors. We evaluated the effects of anti-CTLA-4 given in combination with an antigen-specific dendritic cell vaccine on intratumoral Teffs in a murine pancreatic cancer model. The dendritic cell-targeted tumor antigen plus anti-CTLA-4 significantly increased the number of vaccine-induced CD4+ Teffs within the tumor. This increase was accompanied by a reduction in the size of the peripheral CD4+ Teff pool. We also found that IL-3 production by activated CD4+ T cells was significantly increased with this combination. Importantly, the CD4+ Teff response was attenuated in Il3-/- mice, suggesting mediation of the effect by IL-3. Finally, the induced T cell infiltration was associated with activation of the tumor endothelium by T cell-derived IL-3. Our findings collectively provide a new insight into the mechanism driving Teff infiltration and vascular activation in a murine pancreatic cancer model, specifically identifying a new role for IL-3 in the anticancer immune response.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Vacinas Anticâncer/imunologia , Interleucina-3/imunologia , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Modelos Animais de Doenças , Interleucina-3/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Pancreáticas/imunologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-30893922

RESUMO

The aim of this study was to examine the association between interleukin (IL) genes polymorphisms and in vitro fertilization (IVF) outcome. A prospective cohort analysis was performed at a Women's Hospital IVF centre of 1015 female patients undergoing fresh non-donor IVF cycles. The effects of the following six single nucleotide polymorphisms (SNPs) in five IL genes on IVF outcomes were explored: IL-1α (rs1800587 C/T), IL-3 (rs40401 C/T), IL-6 (rs1800795 C/G), IL-15 (rs3806798 A/T), IL-18 (rs187238 C/G) and IL-18 (rs1946518 G/T). The main outcome measures included clinical pregnancy, embryo implantation, abortion and live birth rates. There were no statistically significant differences in clinical pregnancy, embryo implantation and live birth rates in the analysis of 1015 patients attempting their first cycle of IVF. Infertile women with IL-3 homozygous major genotype had a higher abortion rate than those with heterozygous and homozygous minor genotype (16.5% vs. 7.9%, P = 0.025). In conclusion, our results indicated that the IL-3 rs40401 polymorphism is associated with increased risk of abortion of IVF patients. Future studies with inclusion of other ethnic populations must be conducted to confirm the findings of this study.


Assuntos
Aborto Espontâneo/genética , Fertilização In Vitro , Interleucina-3/genética , Polimorfismo de Nucleotídeo Único , Adulto , Implantação do Embrião , Feminino , Homozigoto , Humanos , Infertilidade Feminina/genética , Gravidez , Resultado da Gravidez , Estudos Prospectivos
16.
Mol Immunol ; 109: 71-80, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870654

RESUMO

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. There are multiple cytokines involved in the process of sepsis. As an important upstream cytokine in inflammation, Interleukin-3 (IL-3) plays a crucial role during sepsis, however, its exact role is unclear. The purpose of this study is to discuss the role of IL-3 and its receptor in cecal ligation and puncture (CLP)-induced sepsis in a rat model. The Cluster of Differentiation 123 (CD123, IL-3 receptor alpha chain, IL-3Rac) antibody (anti-CD123) was used to directly target IL-3's receptor and alleviate the effect of IL-3 in the CLP + anti-CD123 group during the early stage of sepsis. CLP was performed in the CLP and CLP + anti-CD123 groups. The time points of observation included 12 h, 24 h, and 5d after the operation. The results showed that the rats in the CLP + anti-CD123 group had lower levels of lactate, serum tumor necrosis factor-α (TNF-α), Interleukin-1ß (IL-1ß), and Interleukin-6 (IL-6), and also exhibited a higher core temperature, mean arterial pressure (MAP), Oxygenation Index (PO2/FiO2), and end-tidal carbon dioxide (ETCO2) and serum Interleukin-10 (IL-10) levels after CLP than those in the CLP group. Additionally, administration of anti-CD123 led to a stable down-regulation of tyrosine phosphorylation of the IL-3 receptor, a decline in phosphorylation of the Janus kinase 2 (JAK2) protein, and the signal transduction and activation of transcription 5 (STAT5) proteins in lung tissues. Meanwhile, the study revealed that treatment of anti-CD123 can markedly attenuate histological damages in lung and kidney tissues, improve sublingual microcirculation, and prolong survival post sepsis. In conclusion, anti-CD123 reduces mortality and alleviates organ dysfunction by restraining the JAK2-STAT5 signaling pathway and reduces serum cytokines in the development of early sepsis in a rat model induced by CLP.


Assuntos
Ceco/patologia , Receptores de Interleucina-3/antagonistas & inibidores , Sepse/patologia , Sepse/prevenção & controle , Animais , Anticorpos/farmacologia , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-3/metabolismo , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Ligadura , Pulmão/metabolismo , Pulmão/patologia , Masculino , Microcirculação/efeitos dos fármacos , Punções , Ratos Sprague-Dawley , Receptores de Interleucina-3/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Leukemia ; 33(10): 2379-2392, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30877275

RESUMO

CD8+ T cell immunosurveillance is crucial in solid tumors and T cell dysfunction leads to tumor progression. In contrast, the role of CD8+ T cells in the control of leukemia is less clear. We characterized the molecular signature of leukemia stem/progenitor cells (LSPCs) and paired CD8+ T cells in patients with acute myeloid leukemia (AML). Epigenetic alterations via histone deacetylation reduced the expression of immune-related genes in bone marrow (BM)-infiltrating CD8+ T cells. Surprisingly, a silenced gene expression pattern in CD8+ T cells significantly correlated with an improved prognosis. To define interactions between CD8+ T cells and LSPCs, we performed comprehensive correlative network modeling. This analysis indicated that CD8+ T cells contribute to the maintenance/expansion of LSPCs, particularly in favorable risk AML. Functionally, CD8+ T cells in favorable AML induced the expansion of LSPCs by stimulating the autocrine production of important hematopoietic cytokines such as interleukin (IL)-3. In contrast, LSPCs in aggressive AML were characterized by a higher activation of stemness/proliferation-related pathways and develop independent of BM CD8+ T cells. Overall, our study indicates that CD8+ T cells support and expand LSPCs in favorable risk AML whereas intermediate and adverse risk AML possess the intrinsic molecular abnormalities to develop independently.


Assuntos
Medula Óssea/imunologia , Linfócitos T CD8-Positivos/imunologia , Leucemia Mieloide Aguda/imunologia , Células-Tronco/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/fisiologia , Citocinas/imunologia , Humanos , Interleucina-3/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
18.
Drugs ; 79(5): 579-583, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30859413

RESUMO

Tagraxofusp (tagraxofusp-erzs) [Elzonris™] is an intravenously administered CD123-directed cytotoxin (composed of human interleukin-3 and a truncated diphtheria toxin payload) that was developed by Stemline Therapeutics, Inc. for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In December 2018, tagraxofusp received its first global approval in the USA for the treatment of BPDCN in adults and in paediatric patients aged 2 years and older. A centralized registration application for the use of tagraxofusp in patients with BPDCN is under review in the EU. This article summarizes the milestones in the development of tagraxofusp leading to its first global approval for the treatment of BPDCN.


Assuntos
Antineoplásicos/farmacocinética , Toxina Diftérica/farmacocinética , Interleucina-3/farmacocinética , Neoplasias Cutâneas/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Toxina Diftérica/administração & dosagem , Toxina Diftérica/efeitos adversos , Toxina Diftérica/uso terapêutico , Aprovação de Drogas , Feminino , Humanos , Interleucina-3/administração & dosagem , Interleucina-3/efeitos adversos , Interleucina-3/uso terapêutico , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Adulto Jovem
19.
Int J Mol Sci ; 20(4)2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769926

RESUMO

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects of the pathogenesis of a range of disorders, including infectious, neoplastic, autoimmune, allergic and cardiovascular diseases. Consequently, GM-CSF and IL-3 are now being investigated as therapeutic targets for some of these disorders, and some phase I/II clinical trials are already showing promising results. There is also pre-clinical and clinical evidence that GM-CSF can be an effective immunostimulatory agent when being combined with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) in patients with metastatic melanoma as well as in novel cancer immunotherapy approaches. Finally, GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells. Altogether, characterizing GM-CSF and IL-3 as central mediators of innate immune activation is poised to open new therapeutic avenues for several immune-mediated disorders and define their potential in the context of immunotherapies.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Imunidade Inata/genética , Interleucina-3/genética , Melanoma/genética , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Humanos , Imunoterapia/tendências , Melanoma/imunologia , Melanoma/terapia , Camundongos
20.
In Vivo ; 33(2): 303-311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804107

RESUMO

AIM: To demonstrate that Fanconi anemia complementation group D2-deficient (Fancd2-/-) hematopoietic progenitor cell lines can be transformed by transfection with a plasmid containing either the E6 or E7 oncogene of human papillomavirus (HPV) to generate malignant plasmacytoma-inducing cell lines. MATERIALS AND METHODS: In order to determine whether a single HPV type 16 (HPV16) oncogene induced malignant transformation, Fancd2-/- and Fancd2+/+ interleukin 3 (IL3)-dependent hematopoietic progenitor cell lines were transfected with plasmids containing E6 or E7 oncogene, or control empty plasmid. RESULTS: Fancd2-/- but not Fancd2+/+ cells were transformed into malignant IL3-independent cells by both E6, and E7 oncogenes, but not by empty plasmid. Hematopoietic cell lines and tumors induced by Fancd2-/- E6 and Fancd2-/- E7 cell lines were positive for each respective HPV RNA and protein. CONCLUSION: A single HPV16 oncogene is adequate to produce malignant transformation of Fancd2-/- hematopoietic cells.


Assuntos
Transformação Celular Neoplásica/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Células-Tronco Hematopoéticas/virologia , Interleucina-3/genética , Linhagem Celular Tumoral , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Proteínas Oncogênicas Virais/genética , Oncogenes/genética , Proteínas E7 de Papillomavirus/genética , Plasmídeos/genética , Proteínas Repressoras/genética , Transfecção/métodos
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