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1.
Nat Commun ; 12(1): 653, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510147

RESUMO

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.


Assuntos
Carcinoma Pulmonar de Lewis/terapia , Imunoterapia/métodos , Receptores Purinérgicos P2X7/imunologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/imunologia , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Células HEK293 , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-18/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Estrutura Molecular , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Bibliotecas de Moléculas Pequenas/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
2.
J Surg Res ; 257: 468-476, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32896815

RESUMO

BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Obtenção de Tecidos e Órgãos , Animais , Morte , Avaliação Pré-Clínica de Medicamentos , Coração/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Masculino , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/metabolismo , Distribuição Aleatória
3.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 203-211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093784

RESUMO

Interleukin 18 (IL18), a pro-inflammatory cytokine, affects the development and progress of vasculitis. The production, expression, and function of this cytokine are affected by polymorphisms of promoter region of the IL18 gene. In this study, a meta-analysis of the associations between several IL18 polymorphisms and susceptibility to vasculitis was performed. Published literature from PubMed and Embase were retrieved. In total, nine studies comprising 1006 patients with vasculitis and 1499 controls combined, and the investigating the rs187238, rs194618, and rs360719 polymorphisms of the promoter region of the IL18 gene, were included in the meta-analysis. Pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated with fixed-effects model or random-effects model. The recessive model of the rs194618 polymorphism was found to be significantly associated with a high susceptibility to vasculitis (OR = 1.54, 95% CI = 1.02-2.33, P = 0.04), especially in the Mongoloid race, where the A allele of rs194618 was associated with a low risk of the disease (OR = 0.77, 95% CI = 0.62-0.95, P = 0.01). By contrast, the rs187238 and rs360719 polymorphisms were not associated with this inflammatory condition. This meta-analysis showed that some IL18 polymorphisms are associated with susceptibility to vasculitis. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 203-211).


Assuntos
Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Vasculite/genética , Predisposição Genética para Doença , Humanos , Fenótipo , Regiões Promotoras Genéticas , Medição de Risco , Fatores de Risco , Vasculite/diagnóstico , Vasculite/etnologia , Vasculite/imunologia
4.
Nat Commun ; 11(1): 4766, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958778

RESUMO

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inflamação/patologia , Telômero/patologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antibacterianos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Caspase 1/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Criança , Colo/metabolismo , Colo/microbiologia , Colo/patologia , Gastroenteropatias/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/microbiologia , Interleucina-18/genética , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Camundongos Mutantes , Fosforilação , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transdução de Sinais , Telomerase/genética , Telomerase/metabolismo
5.
PLoS One ; 15(9): e0239219, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32941527

RESUMO

Neurodegenerative diseases (NDDs) are increasing serious menaces to human health in the recent years. Despite exhibiting different clinical phenotypes and selective neuronal loss, there are certain common features in these disorders, suggesting the presence of commonly dysregulated pathways. Identifying causal genes and dysregulated pathways can be helpful in providing effective treatment in these diseases. Interestingly, in spite of the considerable researches on NDDs, to the best of our knowledge, no dysregulated genes and/or pathways were reported in common across all the major NDDs so far. In this study, for the first time, we have applied the three-way interaction model, as an approach to unravel sophisticated gene interactions, to trace switch genes and significant pathways that are involved in six major NDDs. Subsequently, a gene regulatory network was constructed to investigate the regulatory communication of statistically significant triplets. Finally, KEGG pathway enrichment analysis was applied to find possible common pathways. Because of the central role of neuroinflammation and immune system responses in both pathogenic and protective mechanisms in the NDDs, we focused on immune genes in this study. Our results suggest that "cytokine-cytokine receptor interaction" pathway is enriched in all of the studied NDDs, while "osteoclast differentiation" and "natural killer cell mediated cytotoxicity" pathways are enriched in five of the NDDs each. The results of this study indicate that three pathways that include "osteoclast differentiation", "natural killer cell mediated cytotoxicity" and "cytokine-cytokine receptor interaction" are common in five, five and six NDDs, respectively. Additionally, our analysis showed that Rps27a as a switch gene, together with the gene pair {Il-18, Cx3cl1} form a statistically significant and biologically relevant triplet in the major NDDs. More specifically, we suggested that Cx3cl1 might act as a potential upstream regulator of Il-18 in microglia activation, and in turn, might be controlled with Rps27a in triggering NDDs.


Assuntos
Redes Reguladoras de Genes , Microglia/imunologia , Doenças Neurodegenerativas/genética , Proteínas Ribossômicas/genética , Ubiquitinas/genética , Quimiocina CXCL1/genética , Humanos , Interleucina-18/genética
6.
PLoS One ; 15(7): e0235295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687504

RESUMO

Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/- provides a new model to study atopic dermatitis.


Assuntos
Dermatite Atópica/genética , Inflamação/genética , Queratina-14/genética , Proteínas do Tecido Nervoso/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Animais , Apoptose/genética , Artrite/genética , Artrite/patologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Imunoglobulina E/genética , Inflamação/patologia , Integrases/genética , Interleucina-18/genética , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , NF-kappa B/genética , Fenótipo , Transdução de Sinais
7.
Cell Prolif ; 53(5): e12816, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32347623

RESUMO

OBJECTIVES: Accumulated evidence suggests that Pin1 contributes to oncogenesis of diverse cancers. However, the underlying mechanism of oncogenic function of Pin1 in PDAC requires further exploration. MATERIALS AND METHODS: IHC was performed using PDAC tissues. Western blot, PCR, immunofluorescence and transwell were performed using cell lines. GSEA were applied for possible downstream pathways. ChIP assay and dual luciferase were used for assessment of transcriptional activity. RESULTS: Both Pin1 and IL-18 levels are increased in primary PDAC tissues and that their levels are positively correlated. High expression of IL-18 is a predictor of poor prognoses. Pin1 promoted pancreatic cancer cell proliferation and motility by increasing IL-18 expression, while Pin1 knockdown also inhibited the tumour-promoting effect of IL-18. Both Pin1 and IL-18 could enhance the NFκB activity in pancreatic cancer cells. When bound to the p65 protein, Pin1 promoted p65 phosphorylation and its nuclear translocation. In the nucleus, Pin1 and p65 simultaneously bound to the IL-18 promoter and enhanced IL-18 transcription. In addition, recruitment of p65 to the IL-18 promoter was decreased in Pin1-silenced cells. CONCLUSIONS: Our study improves the understanding of Pin1 in tumour-promoting inflammation in PDAC, which is a hallmark of cancer; Pin1 interacted with p65 in PDAC and enhanced NF-κB signalling and downstream transcriptional activation of IL-18, with increased IL-18 continuously activating NF-κB signalling, which then forms a positive feedback loop.


Assuntos
Interleucina-18/genética , NF-kappa B/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pâncreas/patologia , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Transcrição Genética/genética
8.
Biomol Concepts ; 11(1): 97-101, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32304293

RESUMO

Human papillomavirus (HPV) infection is the most common sexually transmitted infection worldwide. Persistence infection can lead to the development of cervical cancer potentially due to some genetic factors such as polymorphisms in regulatory and coding regions of cytokine genes. The purpose of this study was to determine whether there is a relationship between TNF-308 G/A or IL18 polymorphisms and high-risk HPV infection among sexually active women from Burkina Faso. Ninety-one HPV infected and two hundred and nine HPV negative women (the latter used as healthy controls) were screened. TNFA-308 G/A and IL18-607 C/A polymorphisms were detected using the TaqMan allelic discrimination. HPV 52 (21.19%), HPV 39 (11.86%) and HPV 33 (11.02%) were the most common HPV genotypes. The TNFA-308A and IL18-607 C alleles were predominant in all women in the study. None of the TNFA and IL18 alleles were associated with HPV infection. The results suggest that there is no relationship between TNF-308 G/A or IL18-607C/A polymorphisms and HPV infection among women in the study.


Assuntos
Predisposição Genética para Doença , Interleucina-18/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Burkina Faso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Papillomaviridae/patogenicidade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
9.
Clin Immunol ; 213: 108373, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32135277

RESUMO

Inflammation is a colorectal cancer (CRC) hallmark. Inflammasome-dependent cytokines IL-1ß and IL-18 can play a beneficial or detrimental role in tumorigenesis depending on cancer type. Variants in inflammasome genes were associated with tumor development and/or outcome, and have been proposed as potential biomarkers for population screening. In this study, 215 CRC patients followed-up for 10 years were examined for 9 polymorphisms in selected inflammasome genes. Multivariate association analysis and survival analysis were performed to evaluate the association between the polymorphisms and CRC prognosis. Variants associated with lower levels of IL-18 (rs1834481, rs5744256), or with increased activation of inflammasome receptors NLRP1 (rs12150220) and NLRP3 (rs35829419) resulted detrimental to CRC prognosis and may be used as prognostic markers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Neoplasias Colorretais/genética , Inflamassomos/genética , Interleucina-18/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Reguladoras de Apoptose/imunologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Inflamassomos/imunologia , Interleucina-18/imunologia , Masculino , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Adulto Jovem
10.
Neoplasma ; 67(3): 644-649, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32039628

RESUMO

Interleukin-18 (IL-18) is a multifunctional cytokine that augments interferon-γ production, promotion of the Th1 immune response and acts as an important immunomediator in the development of some cancers. The current study aimed to analyze the association of the five most common polymorphisms in the IL-18 gene with prostate cancer in the Iranian population. We examined a possible association of IL-18 -137G>C, -607C>A, -656G>T, +105A>C and +127C>T polymorphisms with prostate cancer occurrence by PCR-RFLP assay. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association between IL-18 polymorphisms and prostate cancer. Statistical analysis revealed that individuals carrying the mutant homozygote genotype of IL-18 -607C>A (OR=2.251, 95% CI=1.062-4.768, p=0.034) and -137G>C (OR=2.364, 95% CI=1.121-4.984, p=0.024) polymorphisms had an increased risk of prostate cancer. However, for IL-18 -656G>T, +105A>C and +127C>T polymorphisms, there were no differential distributions of their genotypes between patients with prostate cancer and healthy subjects. Our results indicated that the IL-18 -137G>C and -607C>A polymorphisms were significantly associated with an increased risk of prostate cancer in the Iranian population. Thus, these polymorphisms might be used as a molecular biomarker in the early diagnosis of prostate cancer.


Assuntos
Predisposição Genética para Doença , Interleucina-18/genética , Neoplasias da Próstata/genética , Genótipo , Humanos , Irã (Geográfico) , Masculino , Polimorfismo de Nucleotídeo Único
11.
Gene ; 737: 144462, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32045661

RESUMO

OBJECTIVE: To investigate the association of single nucleotide polymorphisms (SNPs) at the interleukin (IL)-18 locus with wheat-dependent exercise-induced anaphylaxis (WDEIA) in the Han Chinese population. METHOD: 130 patients with WDEIA and 600 healthy subjects were recruited for this study. Three tag SNPs (rs360729, rs360717 and rs1946518) were selected and genotyped, and total IgE and specific IgE levels were measured using the ImmunoCAP system. RESULTS: After Bonferroni correction, the frequency of the G-allele in rs1946518 in the WDEIA group was significantly higher than that in control group (P = 0.0015). Genotypic distributions of rs1946518 significantly differed between WDEIA and control groups, and compared with the TT genotype, the homozygote GG genotype was associated with a higher risk of WDEIA (P = 0.0031). At position rs1946518, the log-transformed total IgE values were significantly higher in the group with the heterozygous GT genotype than in TT genotype group (P = 0.0024). Haplotype AGG formed by three SNPs alleles occurred significantly more frequently in WDEIA group than in control group (P = 0.003). CONCLUSION: The minor allele G at position rs1946518 might serve as a marker for the risk of WDEIA.


Assuntos
Anafilaxia/etiologia , Grupo com Ancestrais do Continente Asiático/genética , Grupos Étnicos/genética , Exercício Físico , Variação Genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Hipersensibilidade a Trigo/complicações , Adulto , Anafilaxia/genética , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
12.
Int Arch Allergy Immunol ; 181(5): 375-384, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106113

RESUMO

PURPOSE: Reported associations of interleukin-18 (IL-18) single-nucleotide polymorphisms (SNPs) with allergic rhinitis (AR) have been inconsistent, prompting a meta-analysis to obtain more precise estimates. METHODS: We synthesized data from 8 articles and examined 3 IL-18 SNPs. Two SNPs (rs360721 and rs187238), in linkage disequilibrium, were combined and termed RS1. The rs1946518 SNP was analyzed separately (termed RS2). The recessive, dominant, and codominant (multiplicative) genetic models were used to estimate ORs and 95% CIs. Subgroup analysis was ethnicity-based. Sources of heterogeneity were investigated with outlier treatment. Sensitivity analysis was used to assess robustness of the associative effects. Multiple comparisons were Holm-Bonferroni corrected. RESULTS: All significant (pa < 0.05) outcomes indicating increased risks were found in the dominant/codominant models in RS1 and RS2. Five aspects of differences marked the significant African (RS1) and overall (RS2) outcomes: (i) magnitude of effect (ORs): greater (3.01-5.15) versus less (1.20-1.47); (ii) precision of -effects (95% CIs): less (1.07-21.52) versus more (1.01-1.89); (iii) outlier treated: no versus yes; (iv) sensitivity outcomes: nonrobust versus robust (dominant model only); and (v) greater evidential strength for RS2 (pa = 0.002) compared to RS1 (pa = 0.02) rendered RS2 our core finding. These levels of statistical significance for RS1/RS2 enabled both to survive the Holm-Bonferroni correction. CONCLUSIONS: The core outcome indicating a 1.5-fold increased risk could render the IL-18 polymorphisms useful in the clinical genetics of AR. Future studies that could focus on other IL-18 SNPs may find deeper associations with AR than what we found here.


Assuntos
Predisposição Genética para Doença/genética , Interleucina-18/genética , Rinite Alérgica/genética , Humanos , Polimorfismo de Nucleotídeo Único
13.
Gene ; 731: 144352, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935500

RESUMO

Inflammasome complex mediated interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) production may be involved in immunopathogenesis of polycystic ovary syndrome (PCOS). Therefore, this study was conducted to investigate involved inflammasome pathways in PCOS. Therefore, inflammasome genes expression and serum level of IL-1ß were evaluated in 30 patients with confirmed PCOS and 30 women without PCOS. A remarkable increase in expression of the nucleotide binding and oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NALP3), absent in melanoma 2 (AIM2), IL-18 and associated speck-like protein containing a caspase recruitment domain (CARD); (ASC) genes in PCOS were observed (p < 0.05). In contrast, expression level of NALP1, NALP12, NLR family apoptosis inhibitory proteins (NAIP), NLR family caspase recruitment domain (CARD) domain containing 4 (NLRC4) and IL-1ß genes was not significant. Although the IL-1ß protein level in serum of COS patients with BMI ≥ 25 was significantly higher than PCOS patient with BMI < 25, but there was no significant difference in non-PCOS individuals with BMI < 25 or ≥25. Furthermore, significant correlation between expression of AIM2 (r = 0.83, p = 0.032) and NALP3 (r = 0.59, p = 0.0001) was observed with IL-18, while a positive correlation (r = 0.84, p = 0.0001) was revealed between NAIP and IL-1ß. Based on the obtained results on inflammasome components along with increased expression of IL-1ß especially in overweight patients, it can be concluded that IL-18 expression as well as IL-1ß is probably due to activation of AIM2, NALP3 or NAIP inflammasome, which may play a critical role in immunopathology of PCOS.


Assuntos
Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-1beta/genética , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Adulto , Estudos de Casos e Controles , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Interleucina-18/sangue , Interleucina-18/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/imunologia , Adulto Jovem
14.
BMC Oral Health ; 20(1): 12, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937279

RESUMO

BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral disease with unknown molecular pathogenesis. Our preliminary microarray analysis revealed the altered expression of lncRNA Cancer Susceptibility Gene 2 (CASC2) in RAS. We therefore analyzed the role of CASC2 in RAS. METHODS: In this study, plasma samples were obtained from RAS patients and healthy participants. Plasma levels of CASC2 were measured by RT-qPCR. Plasma levels of IL-6 and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). A follow-up study was performed to analyze the role of CASC2 in the recurrence of RAS. RESULTS: In the present study, we found that lncRNA Cancer Susceptibility Gene 2 (CASC2), as well as pro-inflammatory factors interleukin 6 (IL-6) and interleukin 18 (IL-18), were upregulated in plasma of RAS patients compared with healthy participants. Plasma levels of lncRNA CASC2 were positively correlated with plasma levels of IL-6 and IL-18 in RAS patients but not in healthy participants. Compared with pre-treatment levels, plasma levels of lncRNA CASC2, IL-6 and IL-18 were reduced after recovery. A follow-up study showed that patients with high levels of lncRNA CASC2 had a significantly higher recurrence rate. CONCLUSION: LncRNA CASC 2 is upregulated in RAS and predicts the recurrence.


Assuntos
Interleucina-18/genética , Interleucina-6/genética , RNA Longo não Codificante/genética , Estomatite Aftosa/metabolismo , Proteínas Supressoras de Tumor/genética , Estudos de Casos e Controles , China , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Interleucina-18/sangue , Interleucina-6/sangue , Masculino , RNA Mensageiro/metabolismo , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estomatite Aftosa/sangue , Estomatite Aftosa/complicações , Proteínas Supressoras de Tumor/sangue
15.
Immunology ; 159(4): 413-428, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31919846

RESUMO

A growing body of evidence has indicated that the release of nociceptive factors, such as interleukins and chemokines, by activated immune and glial cells has crucial significance for neuropathic pain generation and maintenance. Moreover, changes in the production of nociceptive immune factors are associated with low opioid efficacy in the treatment of neuropathy. Recently, it has been suggested that CC chemokine receptor type 1 (CCR1) signaling is important for nociception. Our study provides evidence that the development of hypersensitivity in rats following chronic constriction injury (CCI) of the sciatic nerve is associated with significant up-regulation of endogenous CCR1 ligands, namely, CCL2, CCL3, CCL4, CCL6, CCL7 and CCL9 in the spinal cord and CCL2, CCL6, CCL7 and CCL9 in dorsal root ganglia (DRG). We showed that single and repeated intrathecal administration of J113863 (an antagonist of CCR1) attenuated mechanical and thermal hypersensitivity. Moreover, repeated administration of a CCR1 antagonist enhanced the analgesic properties of morphine and buprenorphine after CCI. Simultaneously, repeated administration of J113863 reduced the protein levels of IBA-1 in the spinal cord and MPO and CD4 in the DRG and, as a consequence, the level of pronociceptive factors, such as interleukin-1ß (IL-1ß), IL-6 and IL-18. The data obtained provide evidence that CCR1 blockade reduces hypersensitivity and increases opioid-induced analgesia through the modulation of neuroimmune interactions.


Assuntos
Analgésicos/farmacologia , Buprenorfina/farmacologia , Hiperalgesia/tratamento farmacológico , Morfina/farmacologia , Neuralgia/tratamento farmacológico , Receptores CCR1/imunologia , Xantenos/farmacologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/imunologia , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Gânglios Espinais/fisiopatologia , Regulação da Expressão Gênica , Hiperalgesia/genética , Hiperalgesia/imunologia , Hiperalgesia/fisiopatologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Neuralgia/genética , Neuralgia/imunologia , Neuralgia/fisiopatologia , Nociceptividade/efeitos dos fármacos , Peroxidase/genética , Peroxidase/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Ratos , Ratos Wistar , Receptores CCR1/antagonistas & inibidores , Receptores CCR1/genética , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Transdução de Sinais
16.
Surg Oncol ; 32: 99-107, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31983439

RESUMO

Growing evidences have demonstrated a pivotal role of chronic inflammation in oral squamous cell carcinoma (OSCC) through the modulation of inflammatory cells and cytokine production. IL-37 is newly discovered anti-inflammatory member of IL-1 family and can bind to IL-18 receptor to inhibit IL-18 (pro-inflammatory member of IL-1 family) function. Investigation on the balance of IL-18/IL-37 would provide new insights into the function of IL-1 family in OSCC. Thus, serum IL-18 and IL-37 levels of OSCC patients (n = 108), leukoplakia patients (n = 40), and healthy donors (n = 36) were collected to analyze the balance of IL-18 and IL-37, and also determine their diagnostic value and prognostic significance in OSCC. The results showed that OSCC patients had high IL-18 and low IL-37 levels in serum and peripheral blood mononuclear cell (PBMC). The ratio of IL-18/IL-37 in serum efficiently distinguished non-cancer individuals from OSCC patients (cut off value: 2.15). Moreover, patients with high IL-18 and low IL-37 were susceptible to develop advanced tumor stage and lymph node metastasis (Odd ratios of IL-18/IL-37 is 4.903 and 12.613, respectively). Meanwhile, higher IL-18/IL-37 ratio could predict shorter overall survival and disease-free survival of OSCC patients, although it was not an independent prognostic factor. We further analyze the correlations of serum IL-18/IL-37 with immunocytes in peripheral blood and found that high IL-18 level was associated with more CD19+ B cells, while serum IL-37 seem to be associated with reduced percentage of CD3+CD8+ T cells, indicating its balance could change the adaptive immune response. Unexpectedly, we first revealed the different function of IL-18/IL-37 in serum and tumor tissues. High mRNA expression of IL-18 in tumor tissues correlated with low lymph node metastasis rate and low tumor stage, which was contradictory to the pro-tumor role of IL-18 in serum. In conclusion, enhanced ratio of IL-18/IL-37 level in serum could be an efficient biomarker for OSCC. Its balance might regulate CD19+ B cells and CD3+ CD8+ T cells for OSCC progression.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/secundário , Interleucina-18/sangue , Interleucina-1/sangue , Leucócitos Mononucleares/patologia , Neoplasias Bucais/patologia , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/cirurgia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Seguimentos , Humanos , Interleucina-1/genética , Interleucina-18/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/sangue , Neoplasias Bucais/cirurgia , Prognóstico , Taxa de Sobrevida
17.
Microb Pathog ; 139: 103823, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31676365

RESUMO

BACKGROUND: Associations between polymorphisms in interleukin-6 (IL-6)/interleukin-18 (IL-18) and tuberculosis (TB) were already reported by many publications. The aim of this meta-analysis was to better clarify associations between polymorphisms in IL-6/IL-18 and TB by combing the results of all relevant publications. METHODS: Eligible publications were searched from Pubmed, Embase, WOS and CNKI. We used Review Manager to combine the results of individual studies. RESULTS: Twenty-five studies were included in this study. IL-6 rs1800795 (dominant comparison: OR 1.43, 95% CI 1.23-1.67; recessive comparison: OR 0.48, 95% CI 0.35-0.65; allele comparison: OR 1.43, 95% CI 1.27-1.62), IL-18 rs1946518 (dominant comparison: OR 1.19, 95% CI 1.04-1.35; recessive comparison: OR 0.82, 95% CI 0.71-0.96; allele comparison: OR 1.14, 95% CI 1.05-1.24) and IL-18 rs187238 (dominant comparison: OR 1.35, 95% CI 1.15-1.58; allele comparison: OR 1.31, 95% CI 1.14-1.50) polymorphisms were all significantly associated with TB in the total population. Subgroup analyses showed that positive findings for rs1946518, rs187238 and rs1800795 polymorphisms were mainly driven by the Asians. CONCLUSIONS: Collectively, this meta-analysis proved that IL-6 rs1800795, IL-18 rs1946518 and IL-18 rs187238 polymorphisms may confer susceptibility to TB, especially for Asians.


Assuntos
Interleucina-18/genética , Interleucina-6/genética , Polimorfismo Genético , Tuberculose/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Bases de Dados Factuais , Predisposição Genética para Doença , Humanos , Interleucina-18/metabolismo , Interleucina-6/metabolismo , Sensibilidade e Especificidade , Tuberculose/metabolismo
18.
Am J Respir Crit Care Med ; 201(5): 526-539, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710506

RESUMO

Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/ß signaling. JAK/STAT inhibition or IFNß neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFNα/ß. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.Conclusions: Our data indicate that IL-18 (but not IL-1ß) production from human monocytes requires cooperative Toll-like receptor and IFNα/ß signaling. Interference with IFNα/ß expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.


Assuntos
Tolerância Imunológica/imunologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Receptores Toll-Like/imunologia , Adulto , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Modelos Animais de Doenças , Endotoxinas , Expressão Gênica , Humanos , Técnicas In Vitro , Interferon-alfa/efeitos dos fármacos , Interferon beta/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Inibidores de Janus Quinases/farmacologia , Lipopolissacarídeos/farmacologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/metabolismo , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Inibidores do Fator de Necrose Tumoral/farmacologia
19.
Exp Cell Res ; 386(2): 111737, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759058

RESUMO

The presence of elevated T lymphocytic microparticles (TLMPs) during respiratory illness is associated with airway and lung inflammation and epithelial injuries. Although inflammasome and IL-1ß signaling are crucial in airway inflammation, little was known about their regulatory mechanism. We hypothesized that TLMPs trigger inflammasome activation and IL-1ß production in bronchial and alveolar epithelial cells to induce airway and lung inflammation. In this study, TLMPs induced IL-1ß and IL-18 secretion through NLRP3 inflammasome activation and upregulated TLR4 mRNA and protein expression in alveolar (A549) and human airway epithelial (16HBE) cells. Pretreatment with CLI-095, a specific inhibitor of TLR4 signaling, dramatically diminished the TLMP-induced release of IL-1ß and IL-18 by inhibiting the formation of NLRP3/ASC/pro-caspase-1 inflammasome in a dose-dependent manner. The TLMP-induced autophagy inhibition in epithelial cells was dependent on the PI3K/Akt signaling pathway, which significantly increased NLRP3 expression and enhanced TLMP-induced inflammation. TLR4, IL-1ß, and IL-18 proteins harbored in TLMPs were nonessential for the pro-inflammatory effect. In conclusion, TLMPs induce bronchial and alveolar epithelial cell secretion of IL-1ß and IL-18 cytokines by activating the TLR4 and PI3K/Akt signaling pathways and inhibiting autophagy. These effects lead to NLRP3 inflammasome formation and accumulation. TLMPs may be regarded as deleterious markers of airway and lung damage in respiratory diseases.


Assuntos
Micropartículas Derivadas de Células/imunologia , Meios de Cultivo Condicionados/farmacologia , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Células A549 , Anti-Inflamatórios/farmacologia , Brônquios/citologia , Brônquios/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/imunologia , Caspase 1/genética , Caspase 1/imunologia , Linhagem Celular , Micropartículas Derivadas de Células/química , Meios de Cultivo Condicionados/química , Dactinomicina/farmacologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Regulação da Expressão Gênica , Humanos , Inflamassomos/genética , Inflamassomos/imunologia , Inflamação , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/imunologia
20.
J Agric Food Chem ; 68(2): 512-522, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31870150

RESUMO

Host defense peptides (HDPs) are vital mucosal defense effectors of the innate immune response. The expression of HDPs is inducible in epithelial cells by potent endogenous inducers. Herein, our results demonstrate that sodium butyrate (NaB) induces the expression of porcine ß-defensin-3 (pBD3) and porcine epididymis protein 2 splicing variant C (pEP2C) in a dose- and time-dependent manner, without modifying the production of proinflammatory cytokines, in porcine intestinal epithelial cells (IPEC J2). Moreover, NaB promotes toll-like receptor 2 (TLR2) expression. TLR2 silencing inhibits the pBD3 and pEP2C expression induced by NaB but does not abolish the histone deacetylase (HDAC) inhibitory activity of NaB. We found that NaB activated the nuclear factor-κB (NF-κB) pathway. Importantly, the degree of cell confluence governs the regulatory responses but does not affect the HDAC activity of NaB. Furthermore, epidermal growth factor receptor (EGFR), but not the mitogen-activated protein kinase (MAPK) pathway, is vital during the NaB-induced pBD3 and pEP2C regulation process. We also demonstrated that pBD3 overexpression increases interleukin-18 levels. This study showed that NaB simultaneously induces pBD3 and pEP2C via TLR2 and EGFR in IPEC J2 cells without increasing the risk of a harmful inflammatory response.


Assuntos
Ácido Butírico/farmacologia , Receptores ErbB/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Receptor 2 Toll-Like/metabolismo , beta-Defensinas/metabolismo , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Receptores ErbB/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/genética , Interleucina-18/genética , Interleucina-18/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Suínos , Receptor 2 Toll-Like/genética , beta-Defensinas/genética
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