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1.
J Neuroimmunol ; 357: 577628, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130076

RESUMO

We investigated the association between cellular immunity and age-related hearing loss (ARHL) development using three CD4+ T cell fractions, namely, naturally occurring regulatory T cells (Treg), interleukin 1 receptor type 2-expressing T cells (I1R2), and non-Treg non-I1R2 (nTnI) cells, which comprised Treg and I1R2-deleted CD4+ T cells. Inoculation of the nTnI fraction into a ARHL murine model, not only prevented the development of ARHL and the degeneration of spiral ganglion neurons, but also suppressed serum nitric oxide, a source of oxidative stress. Further investigations on CD4+ T cell fractions could provide novel insights into the prevention of aging, including presbycusis.


Assuntos
Linfócitos T CD4-Positivos/transplante , Presbiacusia/imunologia , Presbiacusia/prevenção & controle , Subpopulações de Linfócitos T/transplante , Animais , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Receptores Tipo II de Interleucina-1/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
2.
J Leukoc Biol ; 108(4): 1199-1213, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32422690

RESUMO

Neutrophils were classically described as powerful effectors of acute inflammation, and their main purpose was assumed to be restricted to pathogen killing through production of oxidants. As consequence, neutrophils also may lead to significant collateral damage to the healthy tissues, and after performing these tasks, these leukocytes are supposed to die within tissues. However, there is a growing body of evidence showing that neutrophils also play a pivotal role in the resolution phases of inflammation, because they can modulate tissue environment due to secretion of different kind of cytokines. Drug-induced liver injury (DILI) is a worldwide concern being one of the most prevalent causes of liver transplantation, and is well established that there is an intense neutrophil recruitment into necrotic liver during DILI. However, information if such abundant granulocyte infiltration is also linked to the tissue repairing phase of hepatic injury is still largely elusive. Here, we investigated the dynamics of neutrophil trafficking within blood, bone marrow, and liver during hepatic inflammation, and how changes in their gene expression profile could drive the resolution events during acetaminophen (APAP)-induced liver injury. We found that neutrophils remained viable during longer periods following liver damage, because they avidly patrolled necrotic areas and up-regulated pro-resolutive genes, including Tgfb, Il1r2, and Fpr2. Adoptive transference of "resolutive neutrophils" harvested from livers at 72 h after injury to mice at the initial phases of injury (6 h after APAP) significantly rescued organ injury. Thus, we provide novel insights on the role of neutrophils not only in the injury amplification, but also in the resolution phases of inflammation.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Fígado/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Fígado/patologia , Camundongos , Neutrófilos/patologia , Receptores de Formil Peptídeo/imunologia , Receptores Tipo II de Interleucina-1/imunologia , Fator de Crescimento Transformador beta/imunologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
3.
Genes (Basel) ; 10(12)2019 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-31817302

RESUMO

Sepsis is a life-threatening disease induced by a systemic inflammatory response, which leads to organ dysfunction and mortality. In sepsis, the host immune response is depressed and unable to cope with infection; no drug is currently available to treat this. The lungs are frequently the starting point for sepsis. This study aimed to identify potential genes for diagnostics and therapeutic purposes in sepsis by a comprehensive bioinformatics analysis. Our criteria are to unravel sepsis-associated signature genes from gene expression datasets. Differentially expressed genes (DEGs) were identified from samples of sepsis patients using a meta-analysis and then further subjected to functional enrichment and protein‒protein interaction (PPI) network analysis for examining their potential functions. Finally, the expression of the topmost upregulated genes (ARG1, IL1R2, ELANE, MMP9) was quantified by reverse transcriptase-PCR (RT-PCR), and myeloperoxidase (MPO) expression was confirmed by immunohistochemistry (IHC) staining in the lungs of a well-established sepsis mouse model. We found that all the four genes were upregulated in semiquantitative RT-PCR studies; however, MMP9 showed a nonsignificant increase in expression. MPO staining showed strong immunoreactivity in sepsis as compared to the control. This study demonstrates the role of significant and widespread immune activation (IL1R2, MMP9), along with oxidative stress (ARG1) and the recruitment of neutrophils, in sepsis (ELANE, MPO).


Assuntos
Regulação da Expressão Gênica/imunologia , Sepse/imunologia , Transcriptoma , Arginase/genética , Arginase/imunologia , Humanos , Elastase de Leucócito/genética , Elastase de Leucócito/imunologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/imunologia , Peroxidase/genética , Peroxidase/imunologia , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/imunologia , Sepse/genética
4.
Cells ; 8(5)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052237

RESUMO

Tendinopathy is accompanied by a cascade of inflammatory events promoting tendon degeneration. Among various cytokines, interleukin-1ß plays a central role in driving catabolic processes, ultimately resulting in the activation of matrix metalloproteinases and a diminished collagen synthesis, both of which promote tendon extracellular matrix degradation. Pulsed electromagnetic field (PEMF) therapy is often used for pain management, osteoarthritis, and delayed wound healing. In vitro PEMF treatment of tendon-derived cells was shown to modulate pro-inflammatory cytokines, potentially limiting their catabolic effects. However, our understanding of the underlying cellular and molecular mechanisms remains limited. We therefore investigated the transcriptome-wide responses of Il-1ß-primed rat Achilles tendon cell-derived 3D tendon-like constructs to high-energy PEMF treatment. RNASeq analysis and gene ontology assignment revealed various biological processes to be affected by PEMF, including extracellular matrix remodeling and negative regulation of apoptosis. Further, we show that members of the cytoprotective Il-6/gp130 family and the Il-1ß decoy receptor Il1r2 are positively regulated upon PEMF exposure. In conclusion, our results provide fundamental mechanistic insight into the cellular and molecular mode of action of PEMF on tendon cells and can help to optimize treatment protocols for the non-invasive therapy of tendinopathies.


Assuntos
Tendão do Calcâneo , Magnetoterapia/métodos , Tendinopatia/terapia , Tendão do Calcâneo/citologia , Tendão do Calcâneo/imunologia , Animais , Apoptose/imunologia , Interleucina-1beta/imunologia , Ratos , Ratos Endogâmicos F344 , Receptores Tipo II de Interleucina-1/imunologia
5.
Mol Biol (Mosk) ; 53(2): 290-302, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31099779

RESUMO

The type 2 interleukin-1 receptor (IL-1R2) is one of natural IL-1ß singling inhibitors in mammals. We cloned and sequenced the IL-1R2 gene in V. variegatus (VvIL-1R2). The phylogenetic analysis showed that the molecular structure VvIL-1R2 is similar to that of its orthologues in other vertebrates. The expression levels of VvIL-1R2 are relatively high in the peripheral blood leukocytes (PBLs), gill, and spleen. In addition, peculiar expression patterns for his molecule were detected at various developmental stages, implying that in flatfishes the IL-1R2 may have be important for embryonic development and metamorphosis. In PBLs, the treatment with pathogen-associated molecular patterns (PAMPs) induced a significant and rapid up-regulation of VvIL-1R2, pointing at its involvement in the immune responses against bacterial and viral pathogens.


Assuntos
Linguado/imunologia , Receptores Tipo II de Interleucina-1/química , Receptores Tipo II de Interleucina-1/imunologia , Animais , Filogenia
6.
Mol Med Rep ; 18(2): 1415-1422, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29901123

RESUMO

Neutrophil­to­lymphocyte ratio (NLR) is commonly considered a useful prognostic index for many cardiovascular diseases; however, it has limited sensitivity and specificity. Factors associated with elevated NLR may aid in the prediction of prognosis with heart failure (HF) in combination with NLR. The present study sought to identify decisive factors associated with NLR in HF patients and investigate their association with elevated NLR. The gene expression profile for blood samples from 197 individuals with chronic heart failure (CHF), with corresponding hematological parameters and clinical data were obtained from the public database, GSE77343. Differentially expressed genes (DEGs) were identified, and Gene Ontology and pathway enrichment analyses were performed. The protein­protein interaction network was constructed with the Search Tool for the Retrieval of Interacting Genes along with Cytoscape. Receiver operating characteristic curves for predictive power, sensitivity and specificity were constructed. The present study identified specific associated DEGs by using Pearson linear correlation and logistic regression analysis. A mean NLR of 3.96 was determined as the cutoff value in the analysis. In total, 31 genes were initially identified as DEGs associated with elevated NLR. They were mainly enriched in neutrophil activation and neutrophil mediated immunity, in fluid shear stress and atherosclerosis, and transcriptional misregulation in cancer. Three focused DEGs, solute carrier family 22 member 4 (SLC22A4), interleukin­1 receptor 2 (IL1R2) and vanin 3 (VNN3), were finally revealed to be independently associated with elevated NLR in CHF patients. The present study demonstrated that the three genes SLC22A4, IL1R2 and VNN3 may be independently associated with elevated NLR in CHF patients as potential decisive factors of NLR.


Assuntos
Amidoidrolases/genética , Moléculas de Adesão Celular/genética , Insuficiência Cardíaca/genética , Linfócitos/metabolismo , Neutrófilos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Receptores Tipo II de Interleucina-1/genética , Idoso , Amidoidrolases/imunologia , Anexina A3/genética , Anexina A3/imunologia , Biomarcadores , Moléculas de Adesão Celular/imunologia , Doença Crônica , Bases de Dados Genéticas , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Humanos , Contagem de Leucócitos , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Neutrófilos/imunologia , Neutrófilos/patologia , Proteínas de Transporte de Cátions Orgânicos/imunologia , Mapeamento de Interação de Proteínas , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/imunologia , Receptores Tipo II de Interleucina-1/imunologia , Simportadores
7.
J Immunol ; 198(7): 2916-2926, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28235865

RESUMO

The biological activity of IL-1 is tightly regulated by the specific receptor antagonist (IL-1Ra) and the decoy receptor IL-1 receptor type 2 (IL-1R2). The role of IL-1Ra has been well demonstrated in IL-1Ra-deficient mice. In contrast, the role of endogenous IL-1R2 remains widely unknown. To define the functional role of endogenous IL-1R2 in the K/BxN serum transfer arthritis model and in IL-1ß- or LPS-induced systemic inflammation in vivo, IL-1R2-/- mice were created and compared with wild type mice. IL-1R2-/- mice bred habitually and exhibited a normal phenotype. IL-1R2 deficiency aggravated arthritis severity and increased mRNA levels for key cytokines and chemokines such as IL-6, IL-1ß, Cxcl-1, and Cxcl-2 significantly in ankles. There was no effect of IL-1R2 deficiency on the cell-autonomous cytokine response to IL-1ß in the tested cell types, i.e., neutrophils, macrophages, and fibroblasts, but IL-1R2 deficiency on neutrophils increased the IL-1-induced response of fibroblasts in trans. Furthermore, IL-1ß induced shedding of IL-1R2 in vivo. Inflammatory responses to IL-1ß and LPS-induced mortality were not different in IL-1R2-/- compared with wild type mice. Our data demonstrate that the decoy receptor IL-1R2 plays an important inhibitory role in local IL-1- and neutrophil-dependent tissue inflammation as shown in the K/BxN serum transfer arthritis model. In contrast to IL-1Ra, IL-1R2 appears to be less crucial for systemic responses to acute administration of IL-1 or LPS.


Assuntos
Artrite Experimental/imunologia , Inflamação/imunologia , Receptores Tipo II de Interleucina-1/imunologia , Animais , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real
8.
Respir Res ; 16: 29, 2015 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-25849954

RESUMO

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a disease associated with a high mortality rate. The initial phase is characterized by induction of inflammatory cytokines and chemokines and influx of circulating inflammatory cells, including macrophages which play a pivotal role in the innate and adaptive immune responses to injury. Growing evidence points to phenotypic heterogeneity and plasticity between various macrophage activation states. METHODS: In this study, gene expression in alveolar macrophages and circulating leukocytes from healthy control subjects and patients with ARDS was assessed by mRNA microarray analysis. RESULTS: Both alveolar macrophages and circulating leukocytes demonstrated up-regulation of genes encoding chemotactic factors, antimicrobial peptides, chemokine receptors, and matrix metalloproteinases. Two genes, the pro-inflammatory S100A12 and the anti-inflammatory IL-1 decoy receptor IL-1R2 were significantly induced in both cell populations in ARDS patients, which was confirmed by protein quantification. Although S100A12 levels did not correlate with disease severity, there was a significant association between early plasma levels of IL-1R2 and APACHE III scores at presentation. Moreover, higher levels of IL-1R2 in plasma were observed in non-survivors as compared to survivors at later stages of ARDS. CONCLUSIONS: These results suggest a hybrid state of alveolar macrophage activation in ARDS, with features of both alternative activation and immune tolerance/deactivation.. Furthermore, we have identified a novel plasma biomarker candidate in ARDS that correlates with the severity of systemic illness and mortality.


Assuntos
Perfilação da Expressão Gênica/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Tipo II de Interleucina-1/genética , Síndrome do Desconforto Respiratório/genética , APACHE , Adulto , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores Tipo II de Interleucina-1/sangue , Receptores Tipo II de Interleucina-1/imunologia , Síndrome do Desconforto Respiratório/sangue , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/imunologia , Proteína S100A12/genética , Índice de Gravidade de Doença
9.
Semin Immunol ; 25(6): 408-15, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24239046

RESUMO

The IL-1 family of ligands and receptors has a central role in both innate and adaptive immune responses and is tightly controlled by antagonists, decoy receptors, scavengers, dominant negative molecules, miRNAs and other mechanisms, acting extracellularly or intracellularly. During evolution, the development of multiple mechanisms of negative regulation reveals the need for tight control of the biological consequences of IL-1 family ligands in order to balance local and systemic inflammation and limit immunopathology. Indeed, studies with gene targeted mice for negative regulators and genetic studies in humans provide evidence for their non-redundant role in controlling inflammation, tissue damage and adaptive responses. In addition, studies have revealed the need of negative regulation of the IL-1 family not only in disease, but also in homeostatic conditions. In this review, the negative regulation mediated by decoy receptors are presented and include IL-1R2 and IL-IL-18BP as well as atypical receptors, which include TIR8/SIGIRR, IL-1RAcPb, TIGIRR-1 and IL-1RAPL. Particular emphasis is given to IL-1R2, since its discovery is the basis for the formulation of the decoy paradigm, now considered a general strategy to counter the primary inflammatory activities of cytokines and chemokines. Emphasis is also given to TIR8, a prototypical negative regulatory receptor having non-redundant roles in limiting inflammation and adaptive responses.


Assuntos
Inflamação/imunologia , Interleucina-1/imunologia , Receptores Tipo II de Interleucina-1/imunologia , Imunidade Adaptativa , Animais , Humanos , Imunidade Inata , Mediadores da Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Macrófagos/imunologia , Camundongos , Receptores de Interleucina-1/imunologia
10.
Dev Comp Immunol ; 41(4): 738-45, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23999049

RESUMO

IL-1 receptor type 2 (IL-1R2) is known as one of natural IL-1ß singling inhibitors in mammals. However, the functional role of IL-1R2 in fish remains largely unknown. In this study, grass carp (Ctenopharyngodon idellus) IL-1R2 (gcIL-1R2) was identified and functionally characterized. Similar to its fish homologs, the deduced protein of gcIL-1R2 possessed two Ig-like domains in its extracellular region but lacked an intracellular signaling domain. The involvement of gcIL-1R2 in immune response was demonstrated by investigating its expression profiles in head kidney and head kidney leukocytes (HKLs) following in vivo bacterial infection and in vitro LPS treatment, respectively. Moreover, recombinant grass carp IL-1ß (rgcIL-1ß) was able to stimulate gcIL-1R2 mRNA expression with a rapid kinetics. This stimulation was possibly dependent on p38, JNK, p42/44 and NF-κB pathways in grass carp HKLs, revealing a new regulatory point of IL-1ß signaling at receptor level in fish. Furthermore, recombinant protein of the gcIL-1R2 extracellular region (rgcIL-1R2) was demonstrated to interact with rgcIL-1ß by using ELISA, elucidating the binding specificity of gcIL-1R2. Importantly, the stimulatory effect of rgcIL-1ß on its own mRNA expression was blocked by rgcIL-1R2 in a dose-dependent manner in grass carp HKLs, providing the evidence for a functional role of IL-1R2 in IL-1ß signaling in teleost. These findings suggested that teleost IL-1R2 may serve as a local naturally occurring inhibitor involving in IL-1ß signaling as seen in mammals.


Assuntos
Carpas/metabolismo , Rim Cefálico/metabolismo , Interleucina-1beta/metabolismo , Leucócitos/metabolismo , Receptores Tipo II de Interleucina-1/metabolismo , Sequência de Aminoácidos , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Sequência de Bases , Carpas/genética , Carpas/imunologia , Carpas/microbiologia , Clonagem Molecular/métodos , DNA Complementar/genética , Rim Cefálico/imunologia , Rim Cefálico/microbiologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leucócitos/imunologia , Dados de Sequência Molecular , Filogenia , RNA Mensageiro/genética , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Transdução de Sinais
11.
Immunity ; 38(2): 285-95, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23395675

RESUMO

Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.


Assuntos
Inflamação/metabolismo , Interleucina-1alfa/genética , Necrose/metabolismo , Precursores de Proteínas/genética , Receptores Tipo II de Interleucina-1/genética , Animais , Calpaína/genética , Calpaína/imunologia , Caspase 1/genética , Caspase 1/imunologia , Linhagem Celular , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Camundongos , Necrose/genética , Necrose/imunologia , Especificidade de Órgãos , Ligação Proteica , Precursores de Proteínas/imunologia , Precursores de Proteínas/metabolismo , Proteólise , Receptores Tipo II de Interleucina-1/imunologia , Receptores Tipo II de Interleucina-1/metabolismo , Transdução de Sinais
12.
J Neuroimmunol ; 250(1-2): 1-8, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22652460

RESUMO

We found that rejuvenation of the recipient immunity by inoculation of young CD4(+) T cells or a fetal thymus graft led to down regulation of the interleukin 1 receptor type II (IL-1R2) gene in CD4(+) T cells and reduced age-related hearing loss and degeneration of the spiral ganglion in SAMP1 mice, a murine model of human senescence. Our studies on the relationship between age-related systemic immune dysfunctions and neurodegeneration mechanisms open up new avenues of treatment of neurosenescence, including presbycusis, for which there is no effective therapy.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Transplante de Tecido Fetal , Presbiacusia/prevenção & controle , Receptores Tipo II de Interleucina-1/biossíntese , Timo/transplante , Envelhecimento , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Modelos Animais de Doenças , Citometria de Fluxo , Hibridização In Situ , Camundongos , Degeneração Neural/genética , Degeneração Neural/imunologia , Degeneração Neural/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Presbiacusia/genética , Presbiacusia/imunologia , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/imunologia , Gânglio Espiral da Cóclea/patologia , Transplante Homólogo , Regulação para Cima
13.
Haematologica ; 97(7): 1014-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22271889

RESUMO

BACKGROUND: Allogeneic hematopoietic cell transplantation is the main curative therapy for patients with chronic myeloid leukemia who do not respond to tyrosine kinase inhibitors. It has been proposed that non-human leukocyte antigen gene polymorphisms influence outcome after hematopoietic cell transplantation and could be used alongside traditional patient-donor and transplant characteristics to create a recipient risk profile associated with allogeneic hematopoietic cell transplantation. DESIGN AND METHODS: A previous study from the European Group for Blood and Marrow Transplantation showed that the absence of recipient tumor necrosis factor receptor II, absence of donor interleukin 10 ATA/ACC and presence of donor interleukin 1 receptor antagonist allele 2 genotypes were associated with decreased survival and increased non-relapse mortality in adult patients with chronic myeloid leukemia undergoing myeloablative human leukocyte antigen-identical sibling transplantation. To explore these associations in unrelated donor transplantation, these polymorphisms were genotyped in 383 adult patients with chronic myeloid leukemia who underwent hematopoietic cell transplantation from unrelated donors matched for 10/10 human leukocyte antigens. RESULTS: The polymorphisms were not associated with overall survival, non-relapse mortality, relapse or acute graft-versus-host disease in the unrelated donor cohort. Comparison of the unrelated donor and human leukocyte antigen-identical sibling cohorts showed differences in survival and clinical characteristics. CONCLUSIONS: We did not confirm that non-human leukocyte antigen polymorphisms were associated with outcomes in myeloablative unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia, possibly because of the strong association between clinical variables and outcome which masked more subtle genetic effects.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA/genética , Antígenos HLA/imunologia , Histocompatibilidade/imunologia , Teste de Histocompatibilidade , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Polimorfismo Genético , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Recidiva , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo , Doadores não Relacionados
14.
Genes Immun ; 13(3): 214-20, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22048455

RESUMO

The etiology of systemic lupus erythematosus (SLE) involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesize that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients, 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed that the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis (RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.


Assuntos
Metilação de DNA , Genoma Humano , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Regiões Promotoras Genéticas , Receptores Tipo II de Interleucina-1/genética , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Epigênese Genética , Redes Reguladoras de Genes , Humanos , Interleucina-10/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores Tipo II de Interleucina-1/imunologia
15.
J Reprod Immunol ; 92(1-2): 68-73, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21958553

RESUMO

Interleukin 1 (IL1) may play an important role in endometriosis-associated pelvic inflammation, and natural specific inhibitors, including soluble IL1 receptor accessory protein (sIL1RAcP) and soluble IL1 receptor type 2 (sIL1R2), are critical for counterbalancing the pleiotropic effects of IL1. The objective of this study was to evaluate the levels of sIL1RAcP, together with those of sIL1R2 and IL1ß, in the peritoneal fluid of women with and without endometriosis. Peritoneal fluid samples were obtained at laparoscopy and assessed by ELISA. sIL1RAcP concentrations were reduced in endometriosis stages I-II and III-IV. sIL1R2 concentrations were decreased, and those of IL1ß were significantly increased in endometriosis stages I-II. sIL1RAcP and sIL1R2 concentrations were significantly decreased in the secretory phase of the menstrual cycle, and IL1ß concentrations were elevated in the proliferative and the secretory phases. sIL1RAcP and sIL1R2 concentrations were reduced in women with endometriosis who were infertile, fertile, suffering from pelvic pain or pain-free. However, IL1ß concentrations were significantly reduced in women with endometriosis who were infertile or had pelvic pain. These changes may exacerbate the local peritoneal inflammatory reaction observed in women with endometriosis and contribute to endometriosis pathophysiology and the major symptoms of this disease.


Assuntos
Líquido Ascítico/metabolismo , Endometriose/imunologia , Proteína Acessória do Receptor de Interleucina-1/metabolismo , Interleucina-1beta/metabolismo , Receptores Tipo II de Interleucina-1/metabolismo , Adulto , Progressão da Doença , Endometriose/fisiopatologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Infertilidade , Inflamação , Proteína Acessória do Receptor de Interleucina-1/genética , Proteína Acessória do Receptor de Interleucina-1/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Ciclo Menstrual , Dor Pélvica , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/imunologia
16.
J Reprod Immunol ; 90(2): 220-6, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21704385

RESUMO

The objective was to assess the impact of genetic variation on cervical cytokine concentrations of interleukin (IL)-1α, IL-1ß, IL-6, IL-8 and tumor necrosis factor alpha (TNF-α), and first, to determine if these variants interact with polymorphisms in Toll-like receptor 4 (TLR4) that were previously shown to associate with pro-inflammatory cervical cytokine concentrations, and second, to determine if findings are affected by bacterial vaginosis (BV). We examined 183 single nucleotide polymorphisms (SNPs) in 13 cytokine genes and receptors for associations with cervical cytokine levels in 188 African American and European American women. We tested for associations of gene-gene interactions between SNPs in TLR4 and cytokine gene and receptor polymorphisms with cervical pro-inflammatory cytokines. None of the single locus associations were significant after correction for multiple testing in either European Americans or African Americans. However, there were significant gene-gene interactions between IL-1R2 rs485127 and two SNPs in TLR4 (rs1554973 and rs7856729) with IL-1ß after correction for multiple testing. Our study demonstrates that interactions between TLR4 and IL-1R2 are associated with cervical pro-inflammatory cytokine concentrations. These results provide important insights into the possible regulatory mechanisms of the inflammatory response in the presence and absence of microbial disorders such as BV. Additionally, the observed differences in allele frequencies between African Americans and those of European descent may partially explain population disparity in pregnancy-related phenotypes that are cytokine concentration-dependent.


Assuntos
Colo do Útero , Citocinas , Epistasia Genética , Polimorfismo de Nucleotídeo Único , Receptores Tipo II de Interleucina-1 , Receptor 4 Toll-Like , Vaginose Bacteriana , Adulto , Negro ou Afro-Americano , Colo do Útero/imunologia , Colo do Útero/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Epistasia Genética/genética , Epistasia Genética/imunologia , Feminino , Humanos , Fenótipo , Gravidez/genética , Gravidez/imunologia , Gravidez/metabolismo , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo II de Interleucina-1/imunologia , Receptores Tipo II de Interleucina-1/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo , Vaginose Bacteriana/genética , Vaginose Bacteriana/imunologia , Vaginose Bacteriana/metabolismo , População Branca
17.
Artigo em Inglês | MEDLINE | ID: mdl-20451651

RESUMO

The type II interleukin-1 receptor (IL-1RII) cDNA was cloned from Japanese flounder (Paralichthys olivaceus) by mRNA differential display (DD-PCR) and rapid amplification of cDNA ends (RACE). The full-length cDNA is 1793 bp in length, including a 100 bp 5'-terminal untranslated region (UTR), a 430 bp 3'-terminal UTR, and a 1263 bp open reading frame (ORF). The ORF encodes 420 amino acid residues with an estimated molecular mass of 46.65 kDa. The protein possesses signature features of the IL-R family, consisting of one N-terminal signal peptide, one transmembrane (TM) domain, two Ig-like domains in its extracellular region, one short cytoplasmic tail of 17 amino acids and four conserved proline residue sites. The predicted amino acid sequence has 65.3%, 52.5% and 51.6% identity with gilthead seabream, rainbow trout and Atlantic salmon IL-1RII, respectively. Phylogenetic analysis supported a close relation to mammalian IL-1RII. Reverse Transcription Polymerase Chain Reaction (RT-PCR) analysis indicated that the IL-1RII gene expression of Japanese flounder was weakly up-regulated and reached the peak expression in the kidney, spleen, and gill at 6 h after infection with Vibrio anguillarum, at 1.9, 2.0 and 1.5 times relative to the uninfected fish, respectively. These results suggest that IL-1RII has a signal transduction function and possibly plays a minor role in immune regulation against bacterial(s) infection in Japanese flounder.


Assuntos
DNA Complementar/genética , Linguado/genética , Receptores Tipo II de Interleucina-1/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Linguado/imunologia , Regulação da Expressão Gênica , Humanos , Camundongos , Dados de Sequência Molecular , Filogenia , Receptores Tipo II de Interleucina-1/química , Receptores Tipo II de Interleucina-1/classificação , Receptores Tipo II de Interleucina-1/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Br J Pharmacol ; 156(7): 1115-23, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19298391

RESUMO

BACKGROUND AND PURPOSE: The inflammatory cytokine interleukin-1 (IL-1) has profound actions in the brain, causing neuronal cell death and exacerbating brain damage. While circulating levels are normally low, IL-1 can be produced on the vascular side of the brain endothelium, and within the brain. The naturally occurring IL-1 receptor antagonist has been administered peripherally in a Phase II trial in acute stroke patients; understanding how IL-1 and IL-1 receptor antagonist penetrate the brain is, therefore, of considerable importance. EXPERIMENTAL APPROACH: An in vitro blood-brain barrier model was generated by co-culture of porcine brain microvascular endothelial cells with astrocytes. The mechanisms of transcellular transport of IL-1beta and IL-1 receptor antagonist were characterized in this model, using endocytosis inhibitors and IL-1 receptor-blocking antibodies. KEY RESULTS: Transcellular IL-1beta and IL-1 receptor antagonist transport was temperature-dependent and IL-1beta was transported with higher affinity than IL-1 receptor antagonist. IL-1beta inhibited IL-1 receptor antagonist transport more potently than IL-1 receptor antagonist inhibited IL-1beta transport. Transport of IL-1beta and IL-1 receptor antagonist was not via adsorptive-mediated endocytosis, although inhibition of microtubule assembly significantly attenuated transport of both cytokines. An antibody directed to the type II IL-1 receptor significantly reduced IL-1beta transport. CONCLUSIONS AND IMPLICATIONS: These results are consistent with IL-1 and IL-1 receptor antagonist being transported across cultured cerebromicrovascular endothelial cells and suggest that IL-1beta transport may occur via a type II IL-1 receptor-dependent mechanism. Understanding IL-1 transport into the brain may have benefits, particularly in enhancing penetration of IL-1 receptor antagonist into the brain.


Assuntos
Barreira Hematoencefálica/metabolismo , Células Endoteliais/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1beta/metabolismo , Microvasos/metabolismo , Animais , Anticorpos/farmacologia , Astrócitos/metabolismo , Transporte Biológico , Encéfalo/irrigação sanguínea , Técnicas de Cocultura , Endocitose/efeitos dos fármacos , Microvasos/citologia , Receptores Tipo I de Interleucina-1/antagonistas & inibidores , Receptores Tipo I de Interleucina-1/imunologia , Receptores Tipo I de Interleucina-1/fisiologia , Receptores Tipo II de Interleucina-1/antagonistas & inibidores , Receptores Tipo II de Interleucina-1/imunologia , Receptores Tipo II de Interleucina-1/fisiologia , Suínos
19.
Mol Immunol ; 44(10): 2772-80, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17234266

RESUMO

Interleukin-1beta (IL-1beta) is the prototypic pro-inflammatory cytokine. All the biological effects of IL-1beta are mediated through interaction with type 1 IL-1 receptor (IL-1RI), whereas another receptor, called type 2 IL-1R (IL-1RII), lacks an intracellular signalling domain and acts as a decoy receptor that down-regulates responses to IL-1beta. Although both receptors are present in bony fish, their expression and biological role in the regulation of IL-1beta activity in non-mammalian vertebrates remain to be established. In this study, a homologue of mammalian IL-1RII was isolated and characterized in the gilthead seabream (Sparus aurata). The seabream IL-1RII harboured two Ig-like domains in its extracellular region and a short cytoplasmic tail lacking a signalling domain. The seabream IL-1RII cDNA showed an unexpectedly long 3'UTR compared with that from other species and contained three ATTTA instability motifs, which seem to be responsible for its relatively short half-life (less than 2h). The expression of seabream IL-1RII was dramatically up-regulated after infection with Vibrio anguillarum in all the immune tissues examined and was even more strongly induced than the IL-1beta gene in the head kidney, spleen and liver. Strikingly, the mRNA levels of IL-1RII were 15-fold higher than those of IL-1beta in the liver, suggesting a role for this organ in the neutralization of IL-1beta leaking into the systemic circulation from the sites of inflammation. In vitro, bacterial DNA and flagellin increased the mRNA levels of IL-1RII in macrophages, while only flagellin was able to weakly induce its expression in acidophilic granulocytes. Finally, the seabream IL-1RII was localized in the plasma membrane when expressed in HEK293 cells and was able to bind IL-1beta.


Assuntos
Doenças dos Peixes/genética , Regulação da Expressão Gênica , Receptores Tipo II de Interleucina-1/genética , Dourada/imunologia , Vibrioses/veterinária , Sequência de Aminoácidos , Animais , Membrana Celular/química , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Humanos , Interleucina-1beta/imunologia , Dados de Sequência Molecular , Filogenia , Receptores Tipo II de Interleucina-1/análise , Receptores Tipo II de Interleucina-1/imunologia , Dourada/genética , Dourada/microbiologia , Transcrição Gênica , Regulação para Cima , Vibrioses/genética , Vibrioses/imunologia
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