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1.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370326

RESUMO

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) - rs755622 and rs5844572 - exhibit prognostic relevance in inflammatory diseases. The aim of this study was to investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT5-8 were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; p = 0.03). Additionally, ≥7 microsatellite repeats were associated with lower fibrosis stages (

Assuntos
Carcinoma Hepatocelular/genética , Predisposição Genética para Doença , Hepatite C Crônica/genética , Oxirredutases Intramoleculares/genética , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/virologia , Estudos de Coortes , Técnicas de Imagem por Elasticidade , Feminino , Expressão Gênica , Frequência do Gene , Hepacivirus/patogenicidade , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico por imagem , Hepatite C Crônica/virologia , Heterozigoto , Homozigoto , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/virologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Polimorfismo Genético , Regiões Promotoras Genéticas , Índice de Gravidade de Doença
2.
Iran J Kidney Dis ; 13(4): 232-236, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31422388

RESUMO

INTRODUCTION: Nephrotic syndrome (NS), a common chronic pediatrickidney disease, is associated with immune system dysfunction.The exact role of MIF -137 G>C gene polymorphism on risk of NSis not clear. The current study aimed to evaluate the relationshipbetween MIF -173 G>C (rs755622) variant and susceptibility to NS. METHODS: This case-control study conducted on 134 children withNS and 141 healthy children. Extraction of genomic DNA fromwhole blood was done using salting out method. Genotyping ofthe MIF -173 G>C polymorphism was performed using polymerasechain reaction restriction fragment length polymorphism (PCRRFLP)method. RESULTS: The findings showed that MIF -173 G>C variant significantlyincreases the risk of NS in codominant (OR = 1.82, 95%CI = 1.08-3.08, P = 0.026, GC vs GG), dominant (OR = 1.90, 95%CI = 1.14-3.16,P = 0.015, GC+CC vs GG), overdominant (OR = 1.75, 95%CI = 1.04-2.94, P = 0.037, GC vs GG+CC) and allele (OR = 1.76, 95%CI = 1.13-2.74, P = 0.014, C vs G) inheritance models. Stratified analysisperformed by sex and response to treatment. The findings revealedthat this variant was associated with increased risk of NS in male.No correlation between the variant and response to treatment wasfound. CONCLUSION: In summary, the results indicated that MIF -137 G>Cis significantly associated with increased risk of NS. More studieswith larger sample size among different ethnicities are needed toverify our findings.


Assuntos
Predisposição Genética para Doença , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Síndrome Nefrótica/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Frequência do Gene , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Fatores Sexuais
3.
Mediators Inflamm ; 2019: 2056085, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360118

RESUMO

Colitis-associated colorectal cancer (CRC) development has been shown to be related to chronically enhanced inflammation. Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that favors inflammatory cytokine production and has chemotactic properties for the recruitment of macrophages (Møs) and T cells. Here, we investigated the role of MIF in the inflammatory response and recruitment of immune cells in a murine model of chemical carcinogenesis to establish the impact of MIF on CRC genesis and malignancy. We used BALB/c MIF-knockout (MIF-/-) and wild-type (WT) mice to develop CRC by administering intraperitoneal (i.p.) azoxymethane and dextran sodium sulfate in drinking water. Greater tumor burdens were observed in MIF-/- mice than in WT mice. Tumors from MIF-/- mice were histologically identified to be more aggressive than tumors from WT mice. The localization of MIF suggests that it is also involved in cell differentiation. The relative gene expression of il-17, measured by real-time PCR, was higher in MIF-/- CRC mice, compared to the WT CRC and healthy MIF-/- mice. Importantly, compared to the WT intestinal epithelium, lower percentages of tumor-associated Møs were found in the MIF-/- intestinal epithelium. These results suggest that MIF plays a role in controlling the initial development of CRC by attracting Møs to the tumor, which is a condition that favors the initial antitumor responses.


Assuntos
Colite/metabolismo , Colite/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Macrófagos/metabolismo , Linfócitos T/metabolismo , Animais , Progressão da Doença , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
4.
Inflamm Res ; 68(10): 877-887, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31342095

RESUMO

OBJECTIVE: Vascular endothelial (VE)-cadherin-mediated adherens junction is critical to maintain endothelial integrity. Besides its role of homophilic intercellular adhesion, VE-cadherin also has a role of outside-in signaling with functional consequences for vascular physiology. However, the nature of these signals remains not completely understood. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were used in cell culture experiments. Confluent HUVECs were treated with VE-cadherin function-blocking antibodies BV9 (50 µg/ml) or IgG control. Antibody array was used to screen for cytokine/chemokine in supernatant. For VE-cadherin knockdown, siRNA transfection was used. ELISA, Western blot, and qRT-PCR were used to confirm the expression of screened cytokine/chemokine. To explore the possible mechanisms, Scr phosphorylation was detected and Scr inhibitor PP2 (1 µM) was used. To investigate in vivo relevance of the findings, BV9 and the indicated neutralizing antibodies were injected into mice and then lung vascular leak and inflammation were examined by Evans blue assay and lung tissue H&E, respectively. RESULTS: Using a non-biased, high-throughout human cytokine/chemokine antibody array, we first found that disruption of VE-cadherin-mediated adhesion by function-blocking antibody BV9 triggered the release of migration inhibitory factor (MIF). This VE-cadherin-mediated release of MIF further confirmed by ELISA with both VE-cadherin blocking antibody and siRNA technique was due to enhanced expression of MIF mRNA, which was mediated by Src kinase activation. In addition, in vivo lung vascular leak induced by VE-cadherin function-blocking antibody was partly alleviated by neutralizing MIF. CONCLUSIONS: VE-cadherin regulates MIF synthesis and release via Src kinase. Our data provide additional evidence to the concept that VE-cadherin transfers intracellular signals to coordinate the state of cell-cell adhesion with gene expression.


Assuntos
Antígenos CD/genética , Caderinas/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Caderinas/imunologia , Caderinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética
5.
Fish Shellfish Immunol ; 93: 39-49, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306763

RESUMO

Macrophage migration inhibitory factor (MIF) dynamically connects innate and adaptive immune systems in vertebrate animals, allowing highly orchestrated systemic responses to various insults. The occurrence of MIF-like genes in non-vertebrate organisms suggests its origin from an ancestral metazoan gene, whose function is still a matter of debate. In the present work, by analyzing available genomic and transcriptomic data from bivalve mollusks, we identified 137 MIF-like sequences, which were classified into three types, based on phylogeny and conservation of key residues: MIF, D-DT, and the lineage-specific type MDL. Comparative genomics revealed syntenic conservation of homologous genes at the family level, the loss of D-DT in the Ostreidae family as well as the expansion of MIF-like genes in the Mytilidae family, possibly underpinning the neofunctionalization of duplicated gene copies. In M. galloprovincialis, MIF and one D-DT were mostly expressed in haemocytes and mantle rim of untreated animals, while D-DT paralogs often showed very limited expression, suggesting an accessory role or their persistence as relict genes.


Assuntos
Mytilidae/genética , Ostreidae/genética , Animais , Evolução Molecular , Fatores Inibidores da Migração de Macrófagos/genética , Filogenia , Análise de Sequência de Proteína
6.
Nat Rev Rheumatol ; 15(7): 427-437, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31197253

RESUMO

The role of macrophage migration inhibitory factor (MIF) in autoimmunity is underscored by data showing that common functional polymorphisms in MIF are associated with disease susceptibility or clinical severity. MIF can regulate glucocorticoid-mediated immunosuppression and has a prominent function in cell survival signalling. Further specific functions of MIF are now being defined in different autoimmune diseases and MIF-targeted biologic therapeutics are in early-stage clinical trials. The unique structure of MIF is also directing the development of small-molecule MIF antagonists. Together, these efforts could provide a means of selectively intervening in pathogenesis and overcoming MIF-related genetic susceptibility to many rheumatic diseases.


Assuntos
Doenças Autoimunes/genética , Autoimunidade , Gerenciamento Clínico , Predisposição Genética para Doença , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo Genético , Medicina de Precisão/métodos , Doenças Autoimunes/terapia , Humanos , Oxirredutases Intramoleculares/biossíntese , Fatores Inibidores da Migração de Macrófagos/biossíntese
7.
Mol Med Rep ; 20(2): 1167-1177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173234

RESUMO

Angiogenesis is a critical process of recovery from cerebrovascular disease. A growing body of evidence has confirmed that microRNAs (miRNAs/miRs) have an important role in the modulation of angiogenesis under physiological and pathological conditions including cerebral ischemia injury (CII). Therefore, the aim of the present study was to explore the function and mechanism of microRNAs in regulating angiogenesis using a cell model of CII. Firstly, a miRNA microarray was performed to analyze miRNA expression in serum samples from patients with cerebral ischemia and the results revealed that miR­451 was one of the miRNAs that was the most significantly downregulated. Subsequently, human umbilical vein endothelial cells (HUVECs) were used as an in vitro model to further explore the mechanisms governing angiogenesis during hypoxia. The results demonstrated that overexpression of miR­451 had a significantly anti­angiogenic effect by suppressing tube formation, migration and wound healing in vitro. By contrast, reducing the expression of miR­451 promoted HUVEC migration and tubulogenesis under normoxic conditions. The present study further identified that macrophage migration inhibitory factor (MIF), an important angiogenic regulator, was a novel target of miR­451 that could reverse the effects of miR­451 on the regulation of angiogenesis in HUVECs under hypoxic or normoxic conditions. These results revealed that downregulation of miR­451 promotes angiogenesis by targeting MIF in hypoxic HUVECs and indicated that miR­451 is a potential candidate for CII therapeutics.


Assuntos
Movimento Celular , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hipóxia/metabolismo , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , MicroRNAs/metabolismo , Neovascularização Fisiológica/genética , Idoso , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Hipóxia/genética , Masculino , MicroRNAs/fisiologia , Pessoa de Meia-Idade , Neovascularização Patológica/genética
8.
Arch Dermatol Res ; 311(8): 589-594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31154458

RESUMO

Alopecia areata (AA) is an organ-specific autoimmune disease that targets the bulb of the hair follicles and results in non-scarring hair loss that can range from patchy lesions to involvement of the entire scalp. AA develops when the hair follicles lose their physiologic state of immune privilege. One of the key factors that help in maintaining this immune privilege by suppressing natural killer cells is macrophage migration inhibitory factor (MIF). Surprisingly, MIF is also known to provoke autoimmunity by upregulating cytokines. To address this dilemma and understand the exact nature of the involvement of MIF in disease pathogenesis we investigated the association of MIF gene polymorphisms (- 173 G > C, rs755622) with AA by conducting a case-control study of 274 subjects. We observed that the frequency of the C allele in the patients was significantly lower than the control group (0.15, 0.23, respectively, p = 0.01) and the combined frequencies of the CC and GC genotypes (dominant Mendelian pattern) had the most prevalent difference between the two groups (odds ratio 0.60, 95% confidence interval 0.36-0.99; p = 0.048).Since the C allele is associated with higher MIF transcription levels, this could infer that MIF is more likely to attribute to the preservation of the immune privilege rather than acting as a proinflammatory factor.


Assuntos
Alopecia em Áreas/genética , Predisposição Genética para Doença , Folículo Piloso/imunologia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adolescente , Adulto , Idoso , Alelos , Alopecia em Áreas/imunologia , Alopecia em Áreas/prevenção & controle , Autoimunidade/genética , Estudos de Casos e Controles , Feminino , Genótipo , Folículo Piloso/patologia , Voluntários Saudáveis , Humanos , Privilégio Imunológico/genética , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
9.
Mol Carcinog ; 58(10): 1809-1821, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31219646

RESUMO

Macrophage migration inhibitory factor (MIF) has been shown to closely associate with the malignant progression of a variety of human carcinomas. However, the role and its underlying molecular mechanisms of MIF in the invasion and metastasis of oral squamous cell carcinoma (OSCC) still remains unclear. Here, we found that MIF silencing reduced the cell proliferation, migration, and invasion, as well as matrix metalloprotein-2 (MMP-2) and MMP-9 in OSCC cells. Overexpression of MMP-2 or MMP-9 restored the migration and invasion of MIF-knockdown cells, indicating that MMP-2 and MMP-9 are downstream targets of MIF. In the xenograft model, MIF silencing inhibited tumor growth and in lymph metastasis model, MIF silencing reduced tumor metastasis. More importantly, immunohistochemistry staining in a tissue microarray (TMA) demonstrated that MIF expression was positively correlated with clinic stage, recurrence, metastasis, and poor prognosis of patients with OSCC as well as with the levels of MMP-2 or MMP-9 in TMA. Therefore, our findings suggest that MIF may promote the invasion and metastasis of OSCC through the activation of MMP-2 and MMP-9 and prompt further investigation into the therapeutic value of MIF for OSCC treatment.


Assuntos
Carcinoma de Células Escamosas/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias Bucais/genética , Idoso , Animais , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico
11.
J Exp Clin Cancer Res ; 38(1): 180, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036057

RESUMO

BACKGROUND: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. METHODS: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. RESULTS: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. CONCLUSION: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Oxirredutases Intramoleculares/genética , Neoplasias Pulmonares/tratamento farmacológico , Fatores Inibidores da Migração de Macrófagos/genética , Receptores Virais/genética , Células A549 , Animais , Carcinogênese/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Dasatinibe/administração & dosagem , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases da Família src/genética
12.
Inflamm Res ; 68(6): 481-491, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30944975

RESUMO

OBJECTIVE AND DESIGN: Respiratory syncytial virus (RSV) is the major cause of infection in children up to 2 years old and reinfection is very common among patients. Tissue damage in the lung caused by RSV leads to an immune response and infected cells activate multiple signaling pathways and massive production of inflammatory mediators like macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine. Therefore, we sought to investigate the role of MIF during RSV infection in macrophages. METHODS: We evaluated MIF expression in BALB/c mice-derived macrophages stimulated with different concentrations of RSV by Western blot and real-time PCR. Additionally, different inhibitors of signaling pathways and ROS were used to evaluate their importance for MIF expression. Furthermore, we used a specific MIF inhibitor, ISO-1, to evaluate the role of MIF in viral clearance and in RSV-induced TNF-α, MCP-1 and IL-10 release from macrophages. RESULTS: We showed that RSV induces MIF expression dependently of ROS, 5-LOX, COX and PI3K activation. Moreover, viral replication is necessary for RSV-triggered MIF expression. Differently, p38 MAPK in only partially needed for RSV-induced MIF expression. In addition, MIF is important for the release of TNF-α, MCP-1 and IL-10 triggered by RSV in macrophages. CONCLUSIONS: In conclusion, we demonstrate that MIF is expressed during RSV infection and controls the release of pro-inflammatory cytokines from macrophages in an in vitro model.


Assuntos
Citocinas/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Macrófagos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Fatores Inibidores da Migração de Macrófagos/genética , Macrófagos/virologia , Camundongos Endogâmicos BALB C , Transdução de Sinais , Carga Viral
13.
Biomed Res Int ; 2019: 7850392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30868074

RESUMO

Chronic periodontitis (CP) is an infection that affects the teeth supporting structure. Macrophage migration inhibitory factor (MIF) is an important effector cytokine of the innate immune system. Due to its functional characteristics, MIF may be involved in the immunopathology of CP. The aim of the present study was to evaluate MIF levels in gingival crevicular fluid (GCF), saliva, and serum of CP patients. A cross-sectional study was conducted on 60 subjects divided into two groups: subjects with CP (n= 30) and periodontally healthy subjects without CP (n=30). MIF was quantified in GCF, saliva, and serum of all participants by enzyme-linked immunosorbent assay. MIF concentrations were higher in GCF, saliva, and serum in the group with CP compared with the group without CP and a higher MIF concentration was observed in GCF (p=0.001) and saliva (p=0.009) in the group with CP. MIF intragroup comparisons between fluids demonstrated significant high levels of MIF in saliva compared with GCF and serum in both study groups (p<0.05). A positive correlation was found between clinical signs and MIF concentration in GCF (p<0.05). There is an association between the MIF and the clinical signs of the disease. Therefore, MIF could have an important role in the pathology and progression of CP.


Assuntos
Periodontite Crônica/genética , Periodontite Crônica/metabolismo , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adulto , Periodontite Crônica/sangue , Periodontite Crônica/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Líquido do Sulco Gengival/imunologia , Líquido do Sulco Gengival/metabolismo , Humanos , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Saliva/imunologia , Saliva/metabolismo
14.
Infect Genet Evol ; 71: 108-115, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30914286

RESUMO

Infection by Trypanosoma brucei gambiense is characterized by a wide array of clinical outcomes, ranging from asymptomatic to acute disease and even spontaneous cure. In this study, we investigated the association between macrophage migrating inhibitory factor (MIF), an important pro-inflammatory cytokine that plays a central role in both innate and acquired immunity, and disease outcome during T. b. gambiense infection. A comparative expression analysis of patients, individuals with latent infection and controls found that MIF had significantly higher expression in patients (n = 141; 1.25 ±â€¯0.07; p < .0001) and latent infections (n = 25; 1.23 ±â€¯0.13; p = .0005) relative to controls (n = 46; 0.94 ±â€¯0.11). Furthermore, expression decreased significantly after treatment (patients before treatment n = 33; 1.40 ±â€¯0.18 versus patients after treatment n = 33; 0.99 ±â€¯0.10, p = .0001). We conducted a genome wide eQTL analysis on 29 controls, 128 cases and 15 latently infected individuals for whom expression and genotype data were both available. Four loci, including one containing the chemokine CXCL13, were found to associate with MIF expression. Genes at these loci are candidate regulators of increased expression of MIF after infection. Our study is the first data demonstrating that MIF expression is elevated in T. b. gambiense-infected human hosts but does not appear to contribute to pathology.


Assuntos
Quimiocina CXCL13/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Locos de Características Quantitativas/imunologia , Trypanosoma brucei gambiense/patogenicidade , Tripanossomíase Africana/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL13/genética , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Guiné , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Pessoa de Meia-Idade , Tripanossomíase Africana/imunologia , Tripanossomíase Africana/patologia , Adulto Jovem
15.
Clin Sci (Lond) ; 133(5): 665-680, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30804219

RESUMO

Ischemic preconditioning (IPC) is an endogenous protection strategy against myocardial ischemia-reperfusion (I/R) injury. Macrophage migration inhibitory factor (MIF) released from the myocardium subjected to brief periods of ischemia confers cardioprotection. We hypothesized that MIF plays an essential role in IPC-induced cardioprotection. I/R was induced either ex vivo or in vivo in male wild-type (WT) and MIF knockout (MIFKO) mice with or without proceeding IPC (three cycles of 5-min ischemia and 5-min reperfusion). Indices of myocardial injury, regional inflammation and cardiac function were determined to evaluate the extent of I/R injury. Activations of the reperfusion injury salvage kinase (RISK) pathway, AMP-activated protein kinase (AMPK) and their downstream components were investigated to explore the underlying mechanisms. IPC conferred prominent protection in WT hearts evidenced by reduced infarct size (by 33-35%), myocyte apoptosis and enzymatic markers of tissue injury, ROS production, inflammatory cell infiltration and MCP1/CCR2 expression (all P<0.05). IPC also ameliorated cardiac dysfunction both ex vivo and in vivo These protective effects were abolished in MIFKO hearts. Notably, IPC mediated further activations of RISK pathway, AMPK and the membrane translocation of GLUT4 in WT hearts. Deletion of MIF blunted these changes in response to IPC, which is the likely basis for the absence of protective effects of IPC against I/R injury. In conclusion, MIF plays a critical role in IPC-mediated cardioprotection under ischemic stress by activating RISK signaling pathway and AMPK. These results provide an insight for developing a novel therapeutic strategy that target MIF to protect ischemic hearts.


Assuntos
Oxirredutases Intramoleculares/metabolismo , Precondicionamento Isquêmico Miocárdico/métodos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Oxirredutases Intramoleculares/deficiência , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/deficiência , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores CCR2/metabolismo , Transdução de Sinais , Remodelação Ventricular
16.
Gene ; 697: 165-174, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30802541

RESUMO

BACKGROUND: This study aimed to investigate the impact of miR-451 on the biological behaviours of colon cancer cells along with its targets interactions. METHOD: The levels of miR-451 were tested in colon cancer cell lines (SW480 and SW48). Multiple functional and immunological assays were performed to analyse miR-451 induced growth changes in-vitro and downstream effects on target proteins. RESULTS: Overexpression of miR-451 in colon cancer cells led to reduced cell proliferation, increased apoptosis and decrease accumulation of the cells at the G0/G1 phase of the cell cycle. In addition, a significant increase in the number of the cells was noted in the G2-M phase of cell cycle. Moreover, miR-451 reduced the expression of Oct-4, Sox-2 and Snail indicating its role in stem cell and epithelial-mesenchymal transition (EMT) regulation. An inverse correlation between miR-451 and macrophage migration inhibitory protein (MIF) protein expression occurred in colon cancer cells. Furthermore, restoration the level of miR-451 in colon cancer cells inhibits tumour spheres formation. CONCLUSION: miR-451 has tumour suppressor effects in vitro, which can inhibit the cancer-related signalling pathways in colon cancer.


Assuntos
Neoplasias do Colo/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal , Genes Supressores de Tumor , Humanos , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Macrófagos/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais
17.
Fish Shellfish Immunol ; 87: 839-846, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30797067

RESUMO

Macrophage migration inhibitory factor (MIF) is a cytokine and plays critical roles in inflammatory and immune responses in vertebrates. However, its functional role in inflammation has not been well studied in invertebrates. In the present study, we cloned and characterized MIF gene from Apostichopus japonicus by RNA-seq and RACE approaches (designated as AjMIF). A 1047 bp fragment representing the full-length cDNA of AjMIF was obtained, including a 5' UTR of 100 bp, an open reading frame (ORF) of 366 bp encoding a polypeptide of 121 amino acids residues with the molecular weight of 13.43 kDa and theoretical isoelectric point of 5.63 and a 3' UTR of 580 bp. SMART analysis showed that AjMIF has conserved MIF domain (2-117aa) similar to its mammalian counterparts. The amino terminal proline residue (P2) and invariant lysine residue (K33) which are critical active sites of tautomerase activity in mammalian MIF were also detected. Phylogenic analysis and multiple alignments have shown that AjMIF shared higher degree of structural conservation and sequence identities with other counterparts from invertebrates and vertebrates. For Vibrio splendidus challenged sea cucumber, the peak expression of AjMIF mRNAs in coelomocytes were detected at 6 h (23.5-fold) and remained at high levels until 24 h (4.01-fold), and returned to normal level at 48 h in comparison with that of the control group. Similarly, a significant increase in the relative mRNA levels of AjMIF was also found in 10 µg mL-1 LPS-exposed primary cultured coelomocytes. Functional analysis indicated that recombinant AjMIF incubation could promote inflammatory response related genes of Ajp105, AjVEGF, AjMMP1 and AjHMGB3 expression by 1.35-fold, 1.36-fold, 1.83-fold and 1.27-fold increase, respectively, which was consistent with the findings in vertebrate MIFs. All these results collectively suggested that AjMIF had a similar function to MIFs in higher animals and might serve as a candidate cytokine in inflammatory regulation in sea cucumber.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Stichopus/genética , Stichopus/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Perfilação da Expressão Gênica , Fatores Inibidores da Migração de Macrófagos/genética , Filogenia , Alinhamento de Sequência , Vibrio/fisiologia
18.
Clin Rheumatol ; 38(6): 1643-1654, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30747392

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) is a complex autoimmune disease, characterized by microvascular lesions, autoimmunity, and fibrosis. It is suggested that MIF participates in the amplification of the proinflammatory process in SSc; moreover, the promoter polymorphisms - 794 CATT5-8 (rs5844572) and - 173G>C (rs755622) in the MIF gene have been associated with an increase in MIF serum levels in several autoimmune diseases. The aim of this study was to analyze the relationship of the - 794 CATT5-8 and - 173G>C MIF polymorphisms with mRNA expression, MIF serum levels, and the Th1/Th2/Th17 cytokine profile in SSc. MATERIALS AND METHODS: A case-control study was carried out that included 50 patients with SSc and 100 control subjects (CS). Both polymorphisms were genotyped by PCR and PCR-RFLP. MIF levels were measured by ELISA kit. The cytokine profile and the MIF mRNA expression were quantified by BioPlex MagPix system and real-time PCR, respectively. RESULTS: An association between the - 794 CATT7 and - 173*C MIF alleles and the 7C haplotype with SSc susceptibility was found (p < 0.05). Also, the 7C haplotype was associated with increased MIF mRNA expression (p = 0.03) in SSc. In addition, an increase of IL-1ß and IL-6 serum levels in SSc patients was found as well as a positive correlation between MIF serum levels and Th1 and Th17 cytokine profiles. CONCLUSION: The MIF 7C haplotype is a susceptibility marker for SSc in the southern Mexican population and is associated with MIF mRNA expression. Moreover, there is a positive correlation between MIF serum levels and Th1 and Th17 inflammatory response in SSc.


Assuntos
Citocinas/sangue , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Oxirredutases Intramoleculares/sangue , Fatores Inibidores da Migração de Macrófagos/sangue , Masculino , México , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
19.
Zhonghua Bing Li Xue Za Zhi ; 48(2): 108-111, 2019 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-30695861

RESUMO

Objective: To investigate the effect of macrophage migration inhibitory factor (MIF) on the biology of glioma U87MG and U251 cells. Methods: Silencing MIF gene expression in U87MG cells by RNA interference was monitored by Western blot. MIF low expressing U251 cells were treated at different concentrations of recombinant human MIF (rhMIF) and scratching test and flow cytometry were used to detect cell migration and apoptosis. The protein expression of bcl-2, bax, AKT, p-AKT was detected by Western blot. Results: The ability of migration and anti-apoptosis of U87MG cells silenced by siRNA decreased significantly, and the expression levels of p-AKT and anti-apoptotic protein bcl-2 also decreased; in contrast, the expression level of apoptosis protein bax increased. With increase of rhMIF treatment concentration, the expression levels of MIF protein, p-AKT and bcl-2 in U251 cells were gradually enhanced, whereas the level of apoptosis protein bax was inhibited. Conclusion: MIF promotes cell migration and inhibits apoptosis of both U87MG and U251 cells, likely through the regulation of PI3K/AKT signaling pathway.


Assuntos
Apoptose , Neoplasias Encefálicas/patologia , Movimento Celular , Glioma/patologia , Fatores Inibidores da Migração de Macrófagos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Inativação Gênica , Glioma/metabolismo , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Proteína X Associada a bcl-2/metabolismo
20.
Biomolecules ; 9(2)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30678084

RESUMO

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto /paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.


Assuntos
Fibroblastos/metabolismo , Fatores Inibidores da Migração de Macrófagos/genética , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Animais , Células Cultivadas , Fibroblastos/patologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais/genética
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