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1.
Artif Cells Nanomed Biotechnol ; 47(1): 3138-3152, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31359795

RESUMO

IL-1α is closely related to the development and metastasis of cancer, and its polymorphisms have been reported affecting the susceptibility of malignancy tumors, yet the conclusions are controversial. Present an overall meta-analysis was performed to reach more general findings. Relevant literature was searched from Google Scholar, Web of Science, PubMed, EMBASE, CNKI database and Wanfang database, and the association among polymorphism and cancer risk was appraised by counting ORs and 95% CIs of overall and stratification analysis. The date from 15,586 cases and 18,430 controls in 40 publications were enrolled. There is significantly upregulated risk leads by rs3783553 in all genetic models, while the same tendency was found in all cancer types. The results also suggest a high risk of cancer susceptibility in patients carried rs1800587 polymorphism, of which draw out form allelic and homozygote models in overall studies, especially for cervical cancer. However, there are no significant results in analysis of rs17561. In a word, IL1A SNPs play an essential role in upregulating cancer susceptibility, and current analysis provides detail date for further study in the future.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-1alfa/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Humanos
2.
J Clin Lab Anal ; 33(6): e22903, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102307

RESUMO

BACKGROUND: Interleukin-1 promotes tumor angiogenesis through VEGF production. The interleukin-1 receptor antagonist can suppress tumors by blocking this effect. METHODS: Immunohistochemistry, WB, and gene sequencing were used to analyze the expression of IL-1RA in esophageal cancer patients. WB was used to detect the expression of IL-1RA and interleukin-1α in esophageal cancer cells. Stable ESCC cell models overexpressing the IL-1RA were constructed. Their cell functions were tested, and their effects on VEGF were examined. RESULTS: IL-1RA is downregulated in primary EC tumors, and this downregulation of IL-1RA is closely related to TNM staging and survival prognosis. The overexpression of IL-1RA increased the proliferation of KYSE410 EC cells, which have a high level of IL-1α expression. Overexpression of IL-1RA in KYSE410 cells promotes a decrease in the expression of VEGF-A. However, IL-1RA expression did not cause any changes in EC9706 cells with low IL-1α expression. CONCLUSION: IL-1RA acts as a tumor suppressor, and its deletion promotes tumor progression by increasing VEGF-A expression in ESCC.


Assuntos
Neoplasias Esofágicas/patologia , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/metabolismo , Idoso , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/genética , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Vet Microbiol ; 232: 128-136, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31030836

RESUMO

The interleukin-1 (IL-1) family of cytokines, particularly IL-1α and IL-1ß, are potent regulators of innate immunity that play key roles in host defense against infection, hence we evaluated the role of these cytokines in the control of brucellosis within RAW 264.7 cells. Marked expression and secretion of IL-1α and IL-1ß were observed during Brucella infection in macrophages. Blocking of IL-1α and IL-1ß reduced induction of IL-10, IL-1ß and TNF, and IL-6 and TNF, respectively. However, interference of IL-1α and not IL-1ß signaling notably augmented susceptibility of macrophages to Brucella infection which indicates that IL-1α is required for a downstream signaling cascade of innate immunity for efficient clearance of Brucella. This protection requires binding to interleukin-1 receptor (IL-1R) mediated by myeloid differentiation factor 88 (MyD88) signaling and associated with increased lysosomal-mediated killing and nitric oxide (NO) production. Expression of pro-inflammatory cytokines was observed to be mediated via NF-κB-p50, HIF-1α and CEBPA, but negatively controlled by CEBPB while transcription of some important phagolysosomal genes was regulated via CEBPA and c-Jun which indicates the important role of these transcription factors in the control of Brucella infection in macrophages via IL-1α signaling pathway.


Assuntos
Brucella abortus/patogenicidade , Interleucina-1alfa/imunologia , Macrófagos/imunologia , Óxido Nítrico/imunologia , Animais , Imunidade Inata , Interleucina-1alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/microbiologia , Camundongos , Viabilidade Microbiana , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Células RAW 264.7 , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
4.
J Periodontal Res ; 54(5): 457-467, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30982982

RESUMO

OBJECTIVE: The aim of this systematic review was to evaluate the quality of reporting and methodology in genetic association studies between IL1A -889 and IL1B +3954 polymorphisms and chronic periodontitis. BACKGROUND: Evidence provided by periodontal research on genetic risk factors is of uttermost importance in clinical practice as a possible diagnostic and prognostic tool for periodontitis. Inadequate reporting of results as well as high risk of bias due to methodological inconsistency hampers the integration of evidence in terms of clinical applicability. METHODS: This review includes case-control studies in humans published between 1997 and July 2017. Searching was conducted through MEDLINE, EMBASE, and search handing. Specific scoring systems have been developed to evaluate the quality of methods and reporting. Each article was scored according to its adequacy, and then, the total number and the percentage of items positively qualified for both methods and reporting were calculated. The quality of methods in studies scoring 0-6, 7-12, and 13-16 was, respectively, considered poor, moderate, and good. For reporting, scores of 0-9, 10-18, and 19-26 were deemed of poor, moderate, and good quality, respectively. Pearson's correlation coefficient was calculated to explore the correlation between the year of publication and the quality in terms of methods and reporting. RESULTS: From the 531 screened studies, 52 met the inclusion criteria and were thus included in the study. The quality of methods and reporting of published genetic association papers on IL1 and chronic periodontitis is moderate. On a scale from 0 to 16, the mean score for methods of the reviewed studies was 8.19 ± 1.93. The items more frequently considered inadequate concerned the handling of confounders in statistical analysis, especially oral hygiene habits, socioeconomic status, subgingival colonization of specific periodontal pathogens, and stress. A significant positive correlation was found between the year of publication and the quality scores in terms of method (r = 0.401, P = 0.003). In terms of reporting, the mean score was 14.83 ± 3.04 on a scale from 0 to 26 and it was considered overall moderate. No statistically significant correlation was found between the year of publication and the quality of reporting (P = 0.266). CONCLUSIONS: The association between IL1A -889 and IL1B +3954 polymorphisms and chronic periodontitis is questionable due to methodological inconsistency. Evidence arising from meta-analysis is unreliable due to high risk of bias and moderate quality in terms of reporting.


Assuntos
Periodontite Crônica , Interleucina-1alfa , Interleucina-1beta , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Editoração , Controle de Qualidade , Estudos de Casos e Controles , Periodontite Crônica/genética , Humanos , Interleucina-1alfa/genética , Interleucina-1beta/genética , Editoração/normas , Reprodutibilidade dos Testes
5.
Tissue Eng Part A ; 25(9-10): 809-820, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30968743

RESUMO

IMPACT STATEMENT: We engineered a synthetic transcription system based on nuclear factor kappa-light-chain-enhancer of activated B cells signaling that can attenuate the effects of the inflammatory cytokine interleukin (IL)-1α in a self-regulating manner. This system responds in a time- and dose-dependent manner to rapidly produce therapeutic levels of IL-1 receptor antagonist (IL-1Ra). The use of lentiviral gene therapy allows this system to be utilized through different transduction methods and in different cell types for a variety of applications. Broadly, this approach may be applicable in developing autoregulated biologic systems for tissue engineering and drug delivery in a range of disease applications.


Assuntos
Produtos Biológicos/metabolismo , Redes Reguladoras de Genes , Genes Sintéticos , Terapia Genética , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1alfa , Engenharia Tecidual , Animais , Células HEK293 , Humanos , Proteína Antagonista do Receptor de Interleucina 1/biossíntese , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1alfa/biossíntese , Interleucina-1alfa/genética , Camundongos
6.
Immunity ; 50(4): 1033-1042.e6, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30926232

RESUMO

Ancient organisms have a combined coagulation and immune system, and although links between inflammation and hemostasis exist in mammals, they are indirect and slower to act. Here we investigated direct links between mammalian immune and coagulation systems by examining cytokine proproteins for potential thrombin protease consensus sites. We found that interleukin (IL)-1α is directly activated by thrombin. Thrombin cleaved pro-IL-1α at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1α on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL-1α in the epidermis. Mice bearing a mutation in the IL-1α thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1α was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.


Assuntos
Coagulação Sanguínea/fisiologia , Sistema Imunitário/imunologia , Interleucina-1alfa/fisiologia , Trombina/fisiologia , Imunidade Adaptativa , Sequência de Aminoácidos , Animais , Plaquetas/metabolismo , Humanos , Imunidade Inata , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Queratinócitos/metabolismo , Macrófagos/metabolismo , Mamíferos/imunologia , Camundongos , Precursores de Proteínas/metabolismo , Seleção Genética , Sepse/imunologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Trombopoese/imunologia , Cicatrização/imunologia
7.
BMC Cancer ; 19(1): 181, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819119

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide, and genetic variations exert distinct roles in its pathogenesis. Single nucleotide polymorphisms (SNPs) in interleukin 1 alpha (IL1A) were reported to be correlated to the susceptibility of diverse cancers. The aim of this study was to assess the association of IL1A SNPs with the risk of colorectal cancer in a Chinese Han population. METHODS: To evaluate the correlation between IL1A polymorphisms and CRC risk, Agena MassARRAY platform was used for genotype determination among 248 CRC patients and 463 controls. The relationships between IL1A variants and CRC susceptibility were examined by logistic regression analysis. Stratified analysis was conducted for the association detection in males and females. Haplotype construction and analysis were applied to evaluate the potential relationship between the genetic block and the risk of CRC. SNP functional exploration was performed with available bioinformatics datasets. RESULTS: After adjusting for age and gender, the "AA" genotype of rs2856838 exhibited a risk association with colorectal cancer in the recessive model (adjusted OR = 1.98, 95% CI: 1.05-3.72, p = 0.036). With stratified analysis, the recessive models of rs3783550 (OR = 2.17, 95% CI: 1.03-4.60, p = 0.043), rs2856838 (OR = 2.58, 95% CI: 1.13-5.87, p = 0.024), rs1609682 (OR = 2.20, 95% CI: 1.04-4.65, p = 0.040), and rs3783521 (OR = 2.13, 95% CI: 1.01-4.49, p = 0.048) revealed significant relationships between these variants and an increased CRC risk only in females. Bioinformatics analysis also revealed the putative functions of the selected SNPs. CONCLUSIONS: This study demonstrated that rs2856838 could influence the susceptibility to CRC in Chinese Han population from northwest China. IL1A variants rs3783550, rs2856838, rs1609682, and rs3783521 were associated with CRC risk only in females.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Predisposição Genética para Doença , Interleucina-1alfa/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Estudos de Casos e Controles , China/epidemiologia , Mapeamento Cromossômico , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Padrões de Herança , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances
8.
Ecotoxicol Environ Saf ; 171: 467-474, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-30639873

RESUMO

Ambient particulate matter (PM) poses a great threat to global health and contributes to pulmonary inflammation. However, the potential mechanism of PM-induced inflammation of the lung remains unclear. Osteopontin (OPN) is a multifunctional protein that reportedly regulates inflammatory responses in different diseases. Here, we explored the expression of OPN with PM exposure in vivo and in vitro and attempted to elucidate the regulatory role of OPN in PM-induced airway inflammation. Our results showed that PM exposure increased the expression of OPN in the bronchial epithelium, serum, and bronchoalveolar lavage fluid (BALF) of mice. Moreover, PM induced OPN expression in human bronchial epithelial cells (HBECs) in a dose and time-dependent manner. In vitro, inflammatory cytokines such as IL-1α and IL-1ß were increased in HBECs with PM exposure via the ERK and JNK signaling pathways. Recombinant human OPN could potentiate PM-induced expression of IL-1α and IL-1ß, while OPN siRNA could alleviate PM-induced inflammatory responses in HBECs. Furthermore, we showed that OPN regulated PM-induced inflammatory cytokines via the ERK and JNK pathways in HBECs. This study shows for the first time the positive effect of OPN on PM-induced airway inflammation and contributes to a better understanding of its potential mechanism of action.


Assuntos
Interleucina-1alfa/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases , Osteopontina/metabolismo , Material Particulado/toxicidade , Animais , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-1alfa/genética , Interleucina-1beta/genética , Masculino , Camundongos Endogâmicos C57BL , Osteopontina/genética
9.
Mol Med Rep ; 19(3): 2413-2420, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30664211

RESUMO

Calprotectin in mucosal epidermal keratinocytes has an important role in fighting microbial infections. S100A8 belongs to the S100 protein family and is a subunit of calprotectin (heterodimer complex of S100A8/A9). Interleukin­1α (IL­1α) is one of the cytokines produced by oral keratinocytes. The primary aims of the present study were to investigate the effect of IL­1α on the expression of S100A8 and its underlying molecular mechanism in oral epithelial cells. Determining the molecular mechanism of the induced expression of S100A8 by IL­1α aims to improve current understanding of the roles of calprotectin during the infection of mucosal epithelial cells. The expression analysis indicated that IL­1α significantly induced the expression of S100A8 in human TR146 epithelial cells at the mRNA and protein levels, respectively. The reporter assay demonstrated that the upregulatory effect of S100A8 induced by IL­1α was dependent on the S100A8 promoter specific region (­165/­111). The results of electrophoresis mobility shift assay and chromatin immunoprecipitation assay also demonstrated that the CCAAT/enhancer binding protein ß (C/EBPß) binding site (­113/­109) in the S100A8 promoter region was involved into the upregulatory effect on the expression of S100A8 induced by IL­1α. Taken together, these results suggested that the activation of the expression of S100A8 induced by IL­1α in TR146 epithelial cells involves a mechanism by which the binding activity of C/EBPß to the specific site (­113/­109) of the S100A8 promoter is increased.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/genética , Calgranulina A/genética , Células Epiteliais/metabolismo , Interleucina-1alfa/genética , Sítios de Ligação/genética , Epiderme/crescimento & desenvolvimento , Epiderme/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Queratinócitos/metabolismo , Mucosa Bucal/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica/genética
10.
Neurosci Lett ; 692: 204-209, 2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30366016

RESUMO

The inflammatory system has been implicated in the pathophysiology of a variety of psychiatric conditions. Individuals with PTSD, depression, and other fear- and anxiety-related disorders exhibit alterations in peripheral circulating inflammatory markers, suggesting dysregulation of the inflammatory system. The relationship between inflammation and PTSD has been investigated almost exclusively in the periphery, and has not been extensively explored in human postmortem brain tissue. Interleukins (ILs) represent a subtype of cytokines and are key signaling proteins in the immune and inflammatory systems. Based on prior research implicating IL signaling in PTSD and depression, we performed a preliminary investigation of IL gene expression in a region of the cortex involved in emotion regulation and PTSD, the dorsolateral prefrontal cortex (dlPFC), using tissue from the newly established VA National PTSD Brain Bank. Gene expression analyses were conducted on post-mortem tissue from the dlPFC from 50 donors: 13 controls, 12 PTSD cases, and 25 depressed cases. RNA was extracted from frozen dlPFC tissue, reverse transcribed to cDNA, and quantitative polymerase chain reaction (qPCR) was performed to assess gene expression of IL1A, IL1B, IL6, IL8, IL10, IL13, and IL15. We found a multiple-testing corrected significant decrease in IL1A expression in the dlPFC for PTSD and depression cases compared to controls (p < 0.005) with age at death, sex, race and RNA integrity number (RIN) included as covariates. To our knowledge this finding is the first demonstration of altered IL expression in brain tissue from deceased individuals with histories of PTSD and/or depression.


Assuntos
Interleucina-1alfa/genética , Córtex Pré-Frontal/metabolismo , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Feminino , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1alfa/biossíntese , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transcriptoma
11.
J Cosmet Dermatol ; 18(1): 333-336, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29498183

RESUMO

BACKGROUND: Despite the several studies suggesting the genetic basis of acne vulgaris, the exact genetic architecture of this very common condition is not yet clear. AIM OF THE WORK: This study aimed to investigate the association between IL-1A (-889) gene polymorphism and acne vulgaris in a sample of patients. SUBJECTS AND METHOD: Blood samples from 100 patients with acne vulgaris and 100 healthy age, sex, and BMI matched controls were obtained. DNA samples were isolated from blood cells, and the PCR-RFLP method was used for genotyping. RESULTS: The genotype distributions of IL-1A (-889) polymorphism were as expected under Hardy-Weinberg equilibrium. T allele was predominant in the patients, while C allele predominated in the control subjects (P value < .001). The frequency of TT genotype in patients was significantly higher than in the control subjects (P value < .001). CT genotype was significantly more frequent in the control subjects compared to patients (P value < .001). Among the 47 patients who reported diet as a risk factor for triggering or exacerbating their lesions, 62.5% had TT genotype (P value = .038). CONCLUSION: IL-1A (-889) gene polymorphism has a role in the pathogenesis of acne vulgaris. We suggest that the triggering or exacerbating effect of diet on acne may be related to IL-1A (-889) gene polymorphism.


Assuntos
Acne Vulgar/genética , Dieta , Interleucina-1alfa/genética , Adolescente , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo Genético , Fatores de Risco , Adulto Jovem
12.
Mol Oral Microbiol ; 34(1)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30407731

RESUMO

This study examined the oral epithelial immunotranscriptome response patterns modulated by oral bacterial planktonic or biofilm challenge. We assessed gene expression patterns when epithelial cells were challenged with a multispecies biofilm composed of Streptococcus gordonii, Fusobacterium nucleatum, and Porphyromonas gingivalis representing a type of periodontopathic biofilm compared to challenge with the same species of planktonic bacteria. Of the 579 human immunology genes, a substantial signal of the epithelial cells was observed to 181 genes. Biofilm challenged stimulated significant elevations compared to planktonic bacteria for IL32, IL8, CD44, B2M, TGFBI, NFKBIA, IL1B, CD59, IL1A, CCL20 representing the top 10 signals comprising 55% of the overall signal for the epithelial cell responses. Levels of PLAU, CD9, IFITM1, PLAUR, CD24, TNFSF10, and IL1RN were all elevated by each of the planktonic bacterial challenge vs the biofilm responses. While the biofilms up-regulated 123/579 genes (>2-fold), fewer genes were increased by the planktonic species (36 [S gordonii], 30 [F nucleatum], 44 [P gingivalis]). A wide array of immune genes were regulated by oral bacterial challenge of epithelial cells that would be linked to the local activity of innate and adaptive immune response components in the gingival tissues. Incorporating bacterial species into a structured biofilm dramatically altered the number and level of genes expressed. Additionally, a specific set of genes were significantly decreased with the multispecies biofilms suggesting that some epithelial cell biologic pathways are down-regulated when in contact with this type of pathogenic biofilm.


Assuntos
Biofilmes , Células Epiteliais/imunologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Transcriptoma/genética , Transcriptoma/imunologia , Imunidade Adaptativa , Antígenos CD59/genética , Antígenos CD59/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Regulação para Baixo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fusobacterium nucleatum/metabolismo , Expressão Gênica/genética , Gengiva/imunologia , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Imunidade Inata , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Microbiota , Boca/microbiologia , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Porphyromonas gingivalis/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Streptococcus gordonii/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima
13.
FASEB J ; 33(2): 2526-2536, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30272996

RESUMO

The IL-1 cytokines are considered among the first family of cytokines that orchestrate acute and chronic inflammatory diseases. Both IL-1ß and IL-1α are members of the IL-1 family; however, their distinct roles in the inflammatory processes remain poorly understood. We explored the role of IL-1α in IL-1ß-activated signaling pathways causing synovial inflammation in rheumatoid arthritis (RA). Using synovial fibroblasts isolated from RA joints, we found that IL-1ß significantly stimulated IL-1α expression, which was selectively inhibited by blocking the NF-κB pathway. Knockdown of IL-1α using small interfering RNA abolished IL-1ß-induced pro-IL-1α and pro-IL-1ß expression and suppressed inflammation. Native and chromatin immunoprecipitation studies showed that IL-1α cooperates in NF-κBp65 binding to the distal region of IL-1α promoter and to the proximal region of IL-1ß promoter upstream of the transcription start site to stabilize their gene transcription. Molecular dynamics simulation of IL-1α or IL-1ß binding to IL-1 receptor showed distinct interaction sites that corroborate with the ability of IL-1α to differentially activate phosphorylation of signaling proteins compared with IL-1ß. Our study highlights the importance of IL-1α in mediating IL-1ß-induced inflammation in addition to maintaining its expression and providing a rationale for targeting IL-1α to minimize the role of IL-1ß in inflammatory diseases like RA.-Singh, A. K., Fechtner, S., Chourasia, M., Sicalo, J., Ahmed, S. Critical role of IL-1α in IL-1ß-induced inflammatory responses: cooperation with NF-κBp65 in transcriptional regulation.


Assuntos
Artrite Reumatoide/patologia , Regulação da Expressão Gênica , Inflamação/patologia , Interleucina-1alfa/metabolismo , Interleucina-1beta/farmacologia , NF-kappa B/metabolismo , Membrana Sinovial/patologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Células Cultivadas , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Interleucina-1alfa/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , Fosforilação , Transdução de Sinais , Membrana Sinovial/metabolismo , Transcrição Genética
14.
Cell Death Dis ; 9(12): 1181, 2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30518914

RESUMO

Mechanical damage on the skin not only affects barrier function but also induces various immune responses, which trigger or exacerbate skin inflammation. However, how mechanical damage-induced skin inflammation is regulated remains incompletely understood. Here, we show that keratinocytes express the long-chain fatty-acid elongase Elovl6. Mice deficient in Elovl6 showed higher levels of cis-vaccenic acid (CVA) in the epidermis and severe skin inflammation induced by mechanical damage due to tape stripping than did wild-type mice. CVA accelerated tape stripping-triggered keratinocyte death and release of danger-associated molecular patterns (DAMPs) such as high-mobility group box 1 protein (HMGB-1) and IL-1α, which induced production of proinflammatory cytokines and chemokines IL-1ß and CXCL-1 by keratinocytes. Our results demonstrate that Elovl6 regulates mechanical damage-triggered keratinocyte death and the subsequent dermatitis.


Assuntos
Acetiltransferases/genética , Dermatite/genética , Epiderme/metabolismo , Queratinócitos/metabolismo , Mecanotransdução Celular , Acetiltransferases/deficiência , Animais , Fenômenos Biomecânicos , Morte Celular/genética , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Dermatite/metabolismo , Dermatite/patologia , Epiderme/patologia , Regulação da Expressão Gênica , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ácidos Oleicos/metabolismo
15.
Exp Biol Med (Maywood) ; 243(13): 1083-1091, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30465622

RESUMO

Abstract: The aim of this study was to investigate the association of five polymorphisms in the IL1A and IL1B genes in Brazilian patients with primary open angle glaucoma (POAG). A case­control study, including 214 unrelated POAG patients and 187 healthy individuals, was conducted to evaluate the frequency of polymorphisms in the IL1A and IL1B genes. Ophthalmic evaluation was performed and genomic DNA was obtained from all participants. Five single nucleotide polymorphisms (SNPs): IL1A (­889C/T: rs1800587:C > T, +4845G/T:rs17561G>T) and IL1B (­31C/T:rs1143627:T > C, ­511C/T:rs16944C>T and +3954C/T:rs1143634:C > T) were genotyped through direct sequencing. The association of individual SNPs was tested using logistic regression. There was an association between the ­31C/T and ­511 C/T polymorphisms in the IL1B gene with POAG (p = 0.002 and p = 0.009, respectively). High linkage disequilibrium was observed between the ­31C/T and ­511C/T polymorphisms. The statistical analysis showed that the T/C haplotype (­31/­511) in the IL1B gene is more frequent in controls (p = 0.011) and the C/T haplotype (­31/­511) is more common in POAG patients (p = 0.018). Among POAG cases, the genotypic distribution of the ­31C/T and ­511 C/T SNPs was significantly different in patients who underwent anti-glaucomatous surgery compared to patients without surgery (p = 0.016 and 0.023, respectively). There was no statistically significant difference for the remaining SNPs between POAG patients and controls. In conclusion, the C allele of the ­31C/T and the T allele of the ­511C/T polymorphisms in the IL1B gene may represent a "risk haplotype" for the development of POAG in Brazilian individuals. Further studies with larger cohorts of patients are necessary to substantiate these findings.


Assuntos
Predisposição Genética para Doença/genética , Glaucoma de Ângulo Aberto/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
16.
Exp Physiol ; 103(12): 1593-1602, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30311699

RESUMO

NEW FINDINGS: What is the central question of this study? The aim was to determine the renoprotective effects of serelaxin in the setting of chronic heart failure. What are the main findings and its importance? Our data indicate that serelaxin can reduce renal fibrosis and inflammation in experimental heart failure. Currently, there are no effective treatments to rescue renal function in heart failure patients, and our data suggest that serelaxin might have the potential to reduce renal fibrosis and inflammation in heart failure. ABSTRACT: Serelaxin has been demonstrated to attenuate renal fibrosis and inflammation in cardiorenal disease. In the present study, we tested the hypothesis that serelaxin can prevent the decline in renal function in dilated cardiomyopathy (DCM) by targeting renal fibrosis and inflammation. Male transgenic mice with DCM (n = 16) and their wild-type littermates (WT; n = 20) were administered either vehicle or serelaxin (500 µg kg-1  day-1 ; subcutaneous minipumps; 8 weeks). Cardiac function was assessed via echocardiography before and during the eighth week of serelaxin treatment. Renal function and inflammation as well as cardiac and renal fibrosis were assessed at the end of the study. Serelaxin had minimal effect on cardiac function (P ≥ 0.99). Tubulointerstitial and glomerular fibrosis were ∼3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P ≤ 0.001). Renal mRNA expression of Tnfα and Il1α were ∼4- and ∼3-fold greater, respectively, in vehicle-treated DCM mice compared with vehicle-treated WT mice (P ≤ 0.05). Tubulointerstitial and glomerular fibrosis were 46 and 45% less, respectively, in serelaxin-treated DCM mice than in vehicle-treated DCM mice (P ≤ 0.01). Renal cortical mRNA expression of Tnfα and Il1α were 56 and 58% less, respectively, in the former group compared with the latter (P ≤ 0.05). The urinary albumin:creatinine ratio was ∼3-fold greater in vehicle-treated DCM mice compared with vehicle-treated WT mice (P = 0.02). The urinary albumin:creatinine ratio was not significantly different between vehicle-treated DCM mice and serelaxin-treated DCM mice (P = 0.38). These data suggest that serelaxin can attenuate renal fibrosis and inflammation and has the potential to exert renoprotective effects in DCM.


Assuntos
Anti-Inflamatórios/farmacologia , Síndrome Cardiorrenal/tratamento farmacológico , Cardiomiopatia Dilatada/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Rim/efeitos dos fármacos , Nefrite/prevenção & controle , Relaxina/farmacologia , Animais , Síndrome Cardiorrenal/patologia , Síndrome Cardiorrenal/fisiopatologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/fisiopatologia , Colágeno/genética , Colágeno/metabolismo , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Rim/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Nefrite/genética , Nefrite/metabolismo , Nefrite/fisiopatologia , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 38(11): 2678-2690, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354247

RESUMO

Objective- Circulating complement factors are activated by tissue damage and contribute to acute brain injury. The deposition of MBL (mannose-binding lectin), one of the initiators of the lectin complement pathway, on the cerebral endothelium activated by ischemia is a major pathogenic event leading to brain injury. The molecular mechanisms through which MBL influences outcome after ischemia are not understood yet. Approach and Results- Here we show that MBL-deficient (MBL-/-) mice subjected to cerebral ischemia display better flow recovery and less plasma extravasation in the brain than wild-type mice, as assessed by in vivo 2-photon microscopy. This results in reduced vascular dysfunction as shown by the shift from a pro- to an anti-inflammatory vascular phenotype associated with MBL deficiency. We also show that platelets directly bind MBL and that platelets from MBL-/- mice have reduced inflammatory phenotype as indicated by reduced IL-1α (interleukin-1α) content, as early as 6 hours after ischemia. Cultured human brain endothelial cells subjected to oxygen-glucose deprivation and exposed to platelets from MBL-/- mice present less cell death and lower CXCL1 (chemokine [C-X-C motif] ligand 1) release (downstream to IL-1α) than those exposed to wild-type platelets. In turn, MBL deposition on ischemic vessels significantly decreases after ischemia in mice treated with IL-1 receptor antagonist compared with controls, indicating a reciprocal interplay between MBL and IL-1α facilitating endothelial damage. Conclusions- We propose MBL as a hub of pathogenic vascular events. It acts as an early trigger of platelet IL-1α release, which in turn favors MBL deposition on ischemic vessels promoting an endothelial pro-inflammatory phenotype.


Assuntos
Plaquetas/metabolismo , Células Endoteliais/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Interleucina-1alfa/metabolismo , Lectina de Ligação a Manose/metabolismo , Artéria Cerebral Média/metabolismo , Ativação Plaquetária , Animais , Morte Celular , Hipóxia Celular , Células Cultivadas , Quimiocina CXCL1/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Hemodinâmica , Humanos , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Interleucina-1alfa/deficiência , Interleucina-1alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Lectina de Ligação a Manose/deficiência , Lectina de Ligação a Manose/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Artéria Cerebral Média/patologia , Artéria Cerebral Média/fisiopatologia , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais
18.
Med Arch ; 72(2): 136-140, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30302033

RESUMO

Background: Currently while, topical minoxidil and oral finasteride are the only medications approved in androgenetic alopecia (AGA), the cause oriented treatment and immunsupressive treatment are being performed in telogen effluvium (TE) and alopecia areata (AA) respectively. Considering the inflammatory factors in the pathogenesis of these three nonscarring alopecia forms, we have formulated a mixture for topical usage composed of six different herbal extracts (HE) which have already known antiinflammatory and antioxidant features. Materials and Methods: In addition to performing the phytochemical analysis of HE, we detected the gene expression level of IL-1α, the crucial hair loss mediator, for the putative efficacy in nonscarring alopecia. Cell proliferation assay was performed by XTT reagent. After determination of non-cytotoxic concentration, HaCaT cells were treated with HE. RNA isolations were carried out from both non-treated and treated cell groups by using TRI-reagent. Gene expressions of IL-1α and as control GAPDH were determined by RT-qPCR analysis. Results: Results were represented as "IL-1α/GAPDH Fold Change". HE solution caused statistically significant downregulation of IL-1α gene expressions (p<0.0001), compared to untreated control cells. HE treatment ended up with 0.1900 fold change for IL-1α. Conclusion: IL-1α is a direct growth inhibitory agent in hair follicles and an important actor in the pathogenesis of AGA , TE, and AA. Considering together the vitamins, flavonoids, and trace elements identified in the phytochemical analyses and downregulation of IL-1α in HaCaT cells, our HE may be an auxiliary agent in the therapy of these three nonscarring alopecia forms.


Assuntos
Alopecia , Regulação para Baixo/efeitos dos fármacos , Interleucina-1alfa , Extratos Vegetais , Administração Tópica , Alopecia/tratamento farmacológico , Alopecia/genética , Alopecia/imunologia , Células Cultivadas , Flavonoides/administração & dosagem , Perfilação da Expressão Gênica/métodos , Preparações para Cabelo/química , Preparações para Cabelo/farmacologia , Humanos , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1alfa/genética , Queratinócitos/efeitos dos fármacos , Fitoterapia/métodos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Oligoelementos/administração & dosagem , Vitaminas/administração & dosagem
19.
PLoS One ; 13(9): e0203216, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30226843

RESUMO

INTRODUCTION: Mucopolysaccharide diseases are a group of lysosomal storage disorders caused by deficiencies of hydrolase enzymes, leading to pathological glycosaminoglycan accumulation. A number of mucopolysaccharidosis (MPS) types are characterised by severe airway disease, the aetiology of which is poorly understood. There is ongoing evidence of significant clinical disease in the long-term despite disease modifying therapeutic strategies, including enzyme-replacement therapy (ERT). To provide a better understanding of this aspect of disease, we have characterised extracellular matrix (ECM) and inflammatory alterations in adenotonsillar tissue samples from 8 MPS patients. METHODS: Adenotonsillar samples from MPS I, IVA and VI ERT treated patients and from a single enzyme naïve MPS IIIA individual were compared to non-affected control samples using quantitative immunohistochemistry, qPCR and biochemical analysis. RESULTS: Significantly increased lysosomal compartment size and total sulphated glycosaminoglycan (p = 0.0007, 0.02) were identified in patient samples despite ERT. Heparan sulphate glycosaminoglycan was significantly elevated in MPS I and IIIA (p = 0.002), confirming incomplete reversal of disease. Collagen IV and laminin α-5 (p = 0.002, 0.0004) staining demonstrated increased ECM deposition within the reticular and capillary network of MPS samples. No significant change in the expression of the pro-inflammatory cytokines IL-1α, IL-6 or TNF-α was seen compared to control. CONCLUSION: This study suggests a role for ECM remodelling contributing to the obstructive phenotype of airway disease in MPS. Current therapeutic strategies with ERT fail to normalise these pathological alterations within adenotonsillar samples. Our findings lend novel insight into the pathological cascade of events, with primarily structural rather than inflammatory changes contributing to the continuing phenotype seen in patients despite current therapeutic regimes.


Assuntos
Terapia de Reposição de Enzimas/métodos , Mucopolissacaridoses/tratamento farmacológico , Tonsila Faríngea/metabolismo , Tonsila Faríngea/patologia , Criança , Pré-Escolar , Matriz Extracelular/metabolismo , Feminino , Humanos , Lactente , Mediadores da Inflamação/metabolismo , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Mucopolissacaridoses/metabolismo , Mucopolissacaridoses/patologia , Mucopolissacaridose I/tratamento farmacológico , Mucopolissacaridose III/tratamento farmacológico , Mucopolissacaridose IV/tratamento farmacológico , Mucopolissacaridose VI/tratamento farmacológico , Tonsila Palatina/metabolismo , Tonsila Palatina/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
J Immunol ; 201(6): 1639-1644, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30082320

RESUMO

Mice homozygous for the Y208N amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1α and IL-1R signaling, we demonstrated a pivotal role for RIPK1, TAK1, and ASK1 in promoting inflammatory disease in Ptpn6spin mice. In the current study we have identified a previously unknown role for CARD9 signaling as a critical regulator for Ptpn6spin-mediated footpad inflammation. Genetic deletion of CARD9 significantly rescued the Ptpn6spin-mediated footpad inflammation. Mechanistically, enhanced IL-1α-mediated signaling in Ptpn6spin mice neutrophils was dampened in Ptpn6spinCard9-/- mice. Collectively, this study identifies SHP-1 and CARD9 cross-talk as a novel regulator of IL-1α-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Dermatite/imunologia , Neutrófilos/imunologia , Transdução de Sinais/imunologia , Substituição de Aminoácidos , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Dermatite/genética , Dermatite/patologia , Modelos Animais de Doenças , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Neutrófilos/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Transdução de Sinais/genética
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