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1.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
2.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788708
3.
Clin Immunol ; 217: 108490, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32492478
4.
Vascular ; 28(5): 629-642, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32366176

RESUMO

OBJECTIVES: Regulatory T cells (Tregs) mediate immunomodulation and protect against atherosclerosis. It is considered that reducing the amount of pro-inflammatory mediators could be achieved by enhancing the anti-inflammatory response, and this may be considered one of the main targets for therapy development. The inhibitory cytokines secreted by Tregs mainly include interleukin-10 (IL-10) and transforming growth factor-beta (TGF-ß). Based on its known immunosuppressive involvement with other inflammatory disorders, we hypothesized that the newly characterized cytokine interleukin-37 (IL-37) might be associated with the inhibitory functions of Treg in atherosclerosis. Immune regulatory functions of IL-37 have not been completely clarified. Accordingly, we speculated that IL-37 might play a regulatory role in the immunosuppression of Tregs in atherosclerotic disease. METHODS: Real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to test gene expression and protein levels of IL-37 in peripheral blood and localized freshly resected arterial tissues from 84 patients with peripheral arterial occlusive disease and 50 non-atherosclerotic subjects. Results were correlated to disease hallmarks. We also evaluated the ability of recombinant IL-37 to modulate Treg cytokine secretion and T cell inhibition in relation to atherosclerotic disorder in vitro.Results: Our results revealed that IL-37 was increased in patients with chronic lower limb atherosclerotic ischemia, compared to non-atherosclerotic controls. In addition, the expression levels of circulating IL-37 correlated with disease severity of chronic lower limb ischemia. Supplementation with rIL-37 augmented levels of released IL-10 and TGF-ß in supernatants of T cells co-cultured with Tregs in the enrolled patients.Conclusions: Results suggest a role for IL-37 in mediating anti-inflammatory functions in the atherosclerotic process, potentially involving enhancement of Treg inhibitory function and anti-inflammatory cytokine secretion with a particularly marked direct response in severe disease.


Assuntos
Interleucina-1/sangue , Isquemia/sangue , Doença Arterial Periférica/sangue , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Interleucina-1/genética , Interleucina-1/farmacologia , Interleucina-10/metabolismo , Isquemia/diagnóstico , Isquemia/imunologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/imunologia , Fenótipo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/metabolismo
5.
Ann Rheum Dis ; 79(4): 536-544, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32114511

RESUMO

OBJECTIVE: Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout. METHODS: Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout. RESULTS: We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10-5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry. CONCLUSION: Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.


Assuntos
Gota/genética , Interleucina-1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Gota/imunologia , Humanos , Técnicas In Vitro , Interleucina-1/imunologia , Interleucina-1/farmacologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/efeitos dos fármacos , Interleucina-8/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Grupo com Ancestrais Oceânicos/genética , Polimorfismo Genético , Proteínas Recombinantes/farmacologia , Ácido Úrico/imunologia , Ácido Úrico/farmacologia
6.
Chem Pharm Bull (Tokyo) ; 68(2): 133-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32009080

RESUMO

C1q/tumor necrosis factor (TNF)-related protein 12 (CTRP12) is a secretory protein that participates in the regulation of glucose and lipid metabolism in obesity and diabetes. Its role in cardiovascular disease, particularly sepsis-induced cardiac injury, is unclear. Here, we stimulated cardiomyocytes with lipopolysaccharide (LPS) to establish an in vitro cardiomyocyte injury model and CTRP12 was overexpressed with an adenovirus delivery system. Overexpression of CTRP12 reduced the transcription and release of pro-inflammatory cytokines from LPS-stimulated cardiomyocytes, including TNFα, interleukin-1 (IL-1), and IL-6. Reactive oxygen species (ROS) level increased and the oxidation/redox system was disturbed in LPS-stimulated cardiomyocytes, as evident from the decrease in superoxide dismutase activity and an increase in reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and malondialdehyde level. CTRP12 overexpression decreased the increasing level of ROS and ameliorated the unbalance in the oxidation/redox system in LPS-stimulated cardiomyocytes. The viability of cardiomyocytes decreased after LPS stimulation, and the cells underwent apoptosis. CTRP12-overexpressing cardiomyocytes showed a decrease in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive cells, and the ratio of B cell lymphoma (Bcl)-1/Bax in these cells was recovered. In comparison with the control group, LPS-stimulated cardiomyocytes showed reduced expression of nuclear factor E2-related factor 2 (NRF2), while CTRP12-overexpressing cardiomyocytes showed elevated NRF2 expression. Small-interfering RNA-mediated silencing of NRF2 expression in cardiomyocytes resulted in the inhibition of the protective effects of CTRP12. Thus, CTRP12 ameliorated injury in LPS-stimulated cardiomyocytes in an NRF2-dependent manner.


Assuntos
Inflamação/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Lipopolissacarídeos/imunologia , Miócitos Cardíacos/imunologia , Regulação para Cima , Adenoviridae/genética , Animais , Linhagem Celular , Células Cultivadas , Regulação para Baixo , Técnicas de Transferência de Genes , Inflamação/imunologia , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
J Immunol Res ; 2020: 6457879, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104716

RESUMO

IL-37 is a cytokine that plays critical protective roles in many metabolic inflammatory diseases, and its therapeutic potential has been confirmed by exogenous IL-37 administration. However, its regulatory mechanisms remain unclear. U937 cells were treated with autophagy-modifying reagents (3-MA, chloroquine, and rapamycin) with or without LPS stimulation. Thereafter, IL-37 expression and autophagic markers (Beclin1, P62/SQSTM1, and LC3) were determined. For regulatory signal pathways, phosphorylated proteins of NF-κB (p65 and IκBα), AP-1 (c-Fos/c-Jun), and MAPK signal pathways (Erk1/2 and p38 MAPK) were quantified, and the agonists and antagonists of MAPK and NF-κB pathways were also used. Healthy human peripheral blood mononuclear cells were treated similarly to confirm our results. Four rhesus monkeys were also administered chloroquine to evaluate IL-37 induction in vivo and its bioactivity on CD4 proliferation and activation. IL-37 was upregulated by rapamycin and chloroquine in both U937 cells and human PBMCs in the presence of LPS. IL-37 was preferentially induced in autophagic cells associated with LC3 conversion. AP-1 and p65 binding motifs could be deduced in the sequence of the IL-37 promoter. Inductive IL-37 expression was accompanied with increased phosphorylated Erk1/2 and AP-1 and could be completely abolished by an Erk1/2 inhibitor or augmented by Erk1/2 agonists. In monkeys, chloroquine increased IL-37 expression, which was inversely correlated with CD4 proliferation and phosphorylated STAT3. IL-37 levels were induced by rapamycin and chloroquine through the LC3, Erk1/2, and NF-κB/AP-1 pathways. Functional IL-37 could also be induced in vivo.


Assuntos
Cloroquina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-1/genética , Sirolimo/farmacologia , Fator de Transcrição AP-1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Sinergismo Farmacológico , Humanos , Interleucina-1/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , NF-kappa B/metabolismo
8.
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
9.
Chemosphere ; 245: 125581, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31846791

RESUMO

Although several genome-wide interaction studies (GWIS) have been performed in specific European populations to understand the missing link between genetic and environmental factors for lung function, GWIS of Asian samples remain rare. Therefore, we performed a GWIS of exposure to air pollution to identify loci for lung function in Korean adult men. A total of 1826 adult men recruited from two health check-up centers were included in the analysis and the annual mean concentrations of ambient particulate matter with an aerodynamic diameter ≤10 µm (PM10) were used. In case of forced vital capacity (FVC), one SNP (rs12312730) that passed our genome-wide threshold of pint < 1 × 10-5 was detected in the intronic region of the BICD1 gene on chromosome 12. In addition, we found two variants (rs6743376 and rs17042888) located near the IL1RN-IL1F10 gene that were involved in the inflammatory response and associated with decreased FVC via interaction with PM10 exposure. A stratified association analysis according to these SNP genotypes showed that PM10 concentrations in subjects with one or two of the risk alleles, compared with those with the non-risk allele, were significantly correlated with a reduction in FVC. This pattern was replicated in another 892 Korean adult samples. The current study reports the first GWIS discovery in an Asian population: the BICD1 and IL1RN-IL1F10 genes may contribute to the decrease in FVC levels by interacting with PM10 exposure.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Poluentes Atmosféricos/toxicidade , Proteínas do Citoesqueleto/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/genética , Material Particulado/toxicidade , Capacidade Vital , Adulto , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Alelos , Grupo com Ancestrais do Continente Asiático , Exposição Ambiental/análise , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Material Particulado/análise , República da Coreia
10.
Int J Mol Sci ; 20(23)2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31801206

RESUMO

Inflammation is a common feature of many neurodegenerative diseases. The treatment of stem cells as a therapeutic approach to repair damage in the central nervous system represents a valid alternative. In this study, using Next-Generation Sequencing (NGS) technology, we analyzed the transcriptomic profile of human Gingival Mesenchymal Stem Cells (hGMSCs) treated with Moringin [4-(α-l-ramanosyloxy)-benzyl isothiocyanate] (hGMSCs-MOR) or with Cannabidiol (hGMSCs-CBD) at dose of 0.5 or 5 µM, respectively. Moreover, we compared their transcriptomic profiles in order to evaluate analogies and differences in pro- and anti-inflammatory pathways. The hGMSCs-MOR selectively downregulate TNF-α signaling from the beginning, reducing the expression of TNF-α receptor while hGMSCs-CBD limit its activity after the process started. The treatment with CBD downregulates the pro-inflammatory pathway mediated by the IL-1 family, including its receptor while MOR is less efficient. Furthermore, both the treatments are efficient in the IL-6 signaling. In particular, CBD reduces the effect of the pro-inflammatory JAK/STAT pathway while MOR enhances the pro-survival PI3K/AKT/mTOR. In addition, both hGMSCs-MOR and hGMSCs-CBD improve the anti-inflammatory activity enhancing the TGF-ß pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Canabidiol/farmacologia , Isotiocianatos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Gengiva/citologia , Gengiva/efeitos dos fármacos , Gengiva/imunologia , Humanos , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinases/genética , Janus Quinases/imunologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Transcriptoma/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861585

RESUMO

We evaluated the in silico expression and circulating levels of interleukin (IL)37 in patients with different forms of multiple sclerosis (MS) and also upon treatment with different disease-modifying drugs. The combined interpretation of the resulting data strengthens and extends the current emerging concept that endogenous IL37 plays an important role in determining onset and progression of MS. The in silico analysis revealed that production of IL37 from cluster of differentiation (CD)4+ T cells from MS patients was reduced in vitro as compared to healthy controls. The analysis of the datasets also demonstrated that "higher" levels of IL37 production from PBMC entailed significant protection from MS relapses. In addition, the in vivo part of the study showed that IL37 was selectively augmented in the sera of MS patients during a relapse and that treatment with the high potency disease-modifying drug fingolimod significantly increased the frequency of patients with circulating blood levels of IL37 (6/9, 66%) as compared to patients receiving no treatment (n = 48) or platform therapy (n = 59) who had levels of IL37 below the limit of the sensitivity of the assay. This finding therefore anticipates that fingolimod may at least partially exert its beneficial effects in MS by upregulating the production of IL37.


Assuntos
Cloridrato de Fingolimode/uso terapêutico , Interleucina-1/sangue , Interleucina-1/genética , Esclerose Múltipla/tratamento farmacológico , Adulto , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Simulação por Computador , Progressão da Doença , Doenças em Gêmeos/tratamento farmacológico , Doenças em Gêmeos/genética , Doenças em Gêmeos/imunologia , Feminino , Cloridrato de Fingolimode/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Recidiva , Gêmeos Monozigóticos/genética , Regulação para Cima
12.
Biomed Res Int ; 2019: 6712591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31886238

RESUMO

Phosphatase and tensin homolog (PTEN) is a critical regulator of tumorigenesis and bone remodeling, which is also found expressed in the periodontal tissues. Periodontitis is one of the most common oral diseases and associated with alveolar bone resorption and tooth loosening in adults. However, the functional relevance of PTEN in periodontitis remains unclear. Here, we report that PTEN plays an essential role in periodontitis. The in vivo results of our study showed a significant decrease of PTEN in the ligature-induced mouse periodontitis model. The function of PTEN in the macrophages was shown to be associated with inflammatory factors interleukin 1 (IL1) and tumor necrosis factor (TNF-α) by using overexpression and silence methods. Further mechanistic studies indicated lack of PTEN-activated IL1 and TNF-α, which increased the number of osteoclasts and led to alveolar bone erosion and loss. Moreover, PTEN nanoparticles could directly inhibit the inflammatory process and bone erosion, suggesting a controlling role of PTEN during bone remodeling. All these data identified the novel function of PTEN as a key factor in periodontitis and bone remodeling.


Assuntos
Perda do Osso Alveolar/metabolismo , PTEN Fosfo-Hidrolase , Periodontite/metabolismo , Animais , Remodelação Óssea/fisiologia , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/fisiologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Cell Biochem Funct ; 37(8): 618-624, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31710117

RESUMO

The aim of this study was to investigate the effect of vaccinia virus expressing IL-37 (VV-IL-37) on cell proliferation, migration and invasion of hepatocellular carcinoma (HCC) and its possible underlying molecular mechanisms. In this study, we constructed a cancer-targeted vaccinia virus carrying the IL-37 gene knocked in the region of the viral thymidine kinase (TK) gene. Human HCC cell lines were assayed in vitro for cell proliferation, migration and invasion. Serum level, relative mRNA level and protein level of IL-37 in HCC cell lines SMMC7721 and Bel7402 were tested by ELISA assay, qRT-PCR and western blot, respectively. The levels of IL-2, IFN-γ and TNF-α in HCC tumor tissues were also analyzed by ELISA. STAT3 and p-STAT3 expression in tumor tissues were determined by western blot. Our results showed that VV-IL-37 efficiently infected and inhibited HCC cells proliferation, migration and invasion via decreasing STAT3 phosphorylation. In vivo, VV-IL-37 expressed IL-37 at a high level in the transplanted tumor, reduced STAT3 activity, and eventually inhibited tumor growth. In conclusion, we demonstrate that VV-IL-37 promotes antitumor immune responses in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Interleucina-1/metabolismo , Neoplasias Hepáticas/patologia , Vírus Vaccinia/fisiologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-1/genética , Interleucina-2/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transplante Heterólogo , Vírus Vaccinia/genética
14.
J Agric Food Chem ; 67(47): 13082-13092, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31671940

RESUMO

Elevated circulating level of the intestinal microbiota-derived l-carnitine metabolite trimethylamine-N-oxide (TMAO) has recently been linked to many chronic diseases. The purpose of our study was to investigate the effects of omega-7-enriched Decaisnea insignis seed oil (DISO) on reducing TMAO formation to prevent the l-carnitine-induced hepatic damage in mice. Feeding of mice with 3% l-carnitine in drinking water clearly increased the serum and urinary levels of TMAO (p < 0.05 vs Normal), whereas the serum and urinary TMAO formation was sharply reduced by DISO administration (p < 0.05). Meanwhile, DISO resulted in strong inhibition against the elevation of hepatic injury marker (AST, ALT, and ALP) activities and dyslipidemia (TC, TG, LDL-C, and HDL-C), as well as liver inflammatory cytokine (IL-1, IL-6, TNF-α, and TNF-ß) release in l-carnitine-fed mice (p < 0.05). As revealed by 16S rDNA gene sequencing, DISO significantly inhibited the l-carnitine-induced elevations in the abundance of Firmicutes, Proteobacteria, and Erysipelotrichaceae and the increases in the proportion of Lactobacillus and Akkermansia, revealing that DISO attenuated the l-carnitine-caused gut dysbiosis. These findings suggested that DISO could alleviate liver dysfunction in l-carnitine-fed mice, which might be due to the protection against TMAO formation by modulating the gut microbiota.


Assuntos
Carnitina/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias/tratamento farmacológico , Magnoliopsida/química , Óleos Vegetais/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Masculino , Metilaminas/efeitos adversos , Camundongos , Sementes/química
15.
Nat Commun ; 10(1): 4700, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619669

RESUMO

The functions of the IL-36 cytokines remain poorly understood. We report a previously unrecognized mechanism whereby IL-36 promotes innate antiviral immunity in mouse and human models of herpes simplex virus-1 (HSV-1) infections. HSV-1 actively suppresses production of type I interferon (IFN); our data reveal that IL-36 overcomes this immune evasion strategy by increasing cellular sensitivity to IFN. IL-36ß deficient mice display impaired IFN responses and poorly restrict viral replication in skin keratinocytes. In mouse and human keratinocytes IL-36 elicits an antiviral state driven by STAT1 and STAT2 via enhanced expression of IFNAR1 and IFNAR2 subunits of the type I IFN receptor. The degree of IFN regulatory factor 1 (IRF1) involvement is species dependent, with IRF1 playing a more prominent role in human cells. Similar mechanisms are activated by IL-1. Overall, IL-36 acts as an antiviral cytokine by potentiating type I IFN signaling and thereby upholds immune responses to viruses that limit the production of IFNs.


Assuntos
Herpes Simples/imunologia , Interferon Tipo I/imunologia , Interleucina-1/imunologia , Receptor de Interferon alfa e beta/genética , Animais , Modelos Animais de Doenças , Herpesvirus Humano 1 , Humanos , Evasão da Resposta Imune , Fator Regulador 1 de Interferon/imunologia , Interleucina-1/genética , Queratinócitos , Camundongos , Camundongos Knockout , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT2/imunologia , Regulação para Cima
16.
Histochem Cell Biol ; 152(6): 467-473, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31584126

RESUMO

IL-37, the anti-inflammatory cytokine of the IL-1 family, plays several key roles in the regulation of autoimmune diseases. Yet, its role in Hashimoto's thyroiditis (HT) is not clear. In the present study, we found that, in tissues from HT patients, most of the follicular epithelial cells were positive for both IL-37 and single Ig IL-1-related receptor (SIGIRR) by immunohistochemical staining, while the infiltrating lymphocytes and other inflammatory cells hardly expressed any. Meanwhile, mRNA expression levels of IL-37 in peripheral blood mononuclear cells (PBMC) of HT patients were significantly higher than those in normal controls measured by quantitative real-time PCR. Finally, we studied the possible role of IL-37 in IFN-γ-stimulated rat FRTL-5 cells. The results showed that IL-1ß, TNF-α, and MCP-1 mRNA levels were significantly decreased, while the expression of IL-4 mRNA was dramatically up-regulated in IFN-γ-stimulated rat thyroid cell line FRTL-5 pre-treated with IL-37. The current study, for the first time, demonstrated that the IL-37 network is involved in Hashimoto's thyroiditis, and IL-37 signaling pathway may ameliorate the excessive autoimmune responses in this chronic lymphocytic thyroiditis.


Assuntos
Doença de Hashimoto/metabolismo , Interleucina-1/metabolismo , Transdução de Sinais , Adulto , Animais , Células Cultivadas , Retroalimentação Fisiológica , Feminino , Humanos , Interleucina-1/análise , Interleucina-1/genética , Pessoa de Meia-Idade , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética , Adulto Jovem
17.
Artigo em Inglês | MEDLINE | ID: mdl-31605582

RESUMO

INTRODUCTION: The present study aimed to assess the presence of main types of microorganisms involved in the aetiopathogenesis of chronic periodontitis with PCR technique and determinates the presence of composite IL-1 genotype and their associations with founded bacteria. MATERIAL AND METHOD: The examined group was consisted from 20 subjects with diagnosed chronic periodontitis and 20 healthy control without periodontitis. Clinical parameters like gingival index (GI), plaque index (PI), bleeding on probing (BOP), periodontal pocket depth (PPD) and clinical attachment lost (CAL) were determinates. Subgingival dental plaque was collected using a sterilized paper point. We used Parodontose Plus test, reverse hybridization kit, for the detection of periodontal marker bacteria, as well as for the detection of composite Interleukin -1 Genotype Results: The most present bacterial species detected from subgingival dental plaque was Treponema denticola and Porfiromonas gingivalis which was present in 65% of examined patients. In relation to the presence of positive genotype in patients, there was no significant difference between the test and control group for p> 0.05 (p = 1.00). For χ2=8,17 (p=0,06, p<0,05) there is an association between Prevotella intermedia, and composite genotype. Between positive genotype and analyzed bacterial species A. actinomycetem comitans for p> 0.05 (p = 1.00), P. gingivalis for p> 0.05 (p = 0.16), T. Forsythia for p> 0.05 (p = 0.20), T. Denticola for p> 0.05 (p = 0.64) no association was found. CONCLUSION: This investigations confirmed the strong association of these five examined periopathogenes with periodontitis.


Assuntos
Periodontite Crônica/microbiologia , Placa Dentária/microbiologia , Interleucina-1/genética , Adulto , Aggregatibacter actinomycetemcomitans/genética , Aggregatibacter actinomycetemcomitans/crescimento & desenvolvimento , Aggregatibacter actinomycetemcomitans/isolamento & purificação , Periodontite Crônica/metabolismo , Placa Dentária/metabolismo , Índice de Placa Dentária , Genótipo , Humanos , Pessoa de Meia-Idade , Índice Periodontal , Bolsa Periodontal/microbiologia , Reação em Cadeia da Polimerase/métodos , Porphyromonas gingivalis/genética , Porphyromonas gingivalis/crescimento & desenvolvimento , Porphyromonas gingivalis/isolamento & purificação , Prevotella intermedia/genética , Prevotella intermedia/crescimento & desenvolvimento , Prevotella intermedia/isolamento & purificação , Treponema denticola/genética , Treponema denticola/crescimento & desenvolvimento , Treponema denticola/isolamento & purificação
18.
Nat Commun ; 10(1): 4003, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488830

RESUMO

Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.


Assuntos
Citocinas/metabolismo , Microbioma Gastrointestinal/fisiologia , Interleucina-1/metabolismo , Doenças Metabólicas/metabolismo , Obesidade/metabolismo , Animais , Colo/imunologia , Colo/microbiologia , Colo/patologia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal/imunologia , Expressão Gênica , Teste de Tolerância a Glucose , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Interleucina-1/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucina-2/metabolismo , Obesidade/imunologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transcriptoma , Verrucomicrobia
19.
Food Funct ; 10(10): 6385-6398, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31513213

RESUMO

This aim of this study is to assess the possible effects of dietary okra seed oil (OSO) consumption on attenuation of alcohol-induced liver damage and gut microbiota dysbiosis, and associated mechanisms in mice. Mice were orally administered alcohol alone or in combination with OSO at 400 and 800 mg per kg bw for 8 weeks. OSO caused a strong inhibition of abnormal weight loss and liver fat accumulation in alcohol-administered mice. Malonaldehyde production was also effectively antagonized, and glutathione peroxidase and superoxide dismutase activities were elevated by OSO treatment in ethanol-based mice (p < 0.05). Concentrations of hepatic TNF-α, IL-1 and IL-6 were decreased after OSO treatment when compared with alcohol-treated mice, respectively (p < 0.05). As revealed by 16S rDNA gene sequence analysis, OSO notably reduced the Proteobacteria proportion and enhanced the Bacteroidetes population of alcohol-treated mice, and a significant reduction in Clostridium XlVa and Staphylococcus was observed, revealing that OSO attenuated the alcohol-induced gut dysbiosis. OSO also attenuated lipid metabolic disorder by modulating metabolism of serum free fatty acids in ethanol-based mice, but had no significant difference in cecum total short-chain fatty acids among the tested mice. Amelioration of these parameters and liver injury via H&E staining examination demonstrated that OSO consumption could effectively protect against liver damage and maintain intestinal eubiosis in mice.


Assuntos
Abelmoschus/química , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Óleos Vegetais/administração & dosagem , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Disbiose/genética , Disbiose/metabolismo , Disbiose/microbiologia , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Sementes/química
20.
BMC Complement Altern Med ; 19(1): 195, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366385

RESUMO

BACKGROUND: Probiotics have been reported to be the active component used in the treatment of many functional gastrointestinal symptoms and syndromes. Lactobacillus and yeast culture are extensively used in probiotic supplements and traditional treatments for irritable bowel syndrome (IBS). The aim of this study was to investigate the effects of probiotic treatments (Lactobacillus acidophilus LA5, Bifidobacterium animalis subsp. lactis BB12 and Saccharomyces cerevisiae var. boulardii) on the behavioral response, targeted gene expression and pro-inflammatory cytokine levels of Pi (Post infectious)-IBS -induced mice. METHODS: Pathogen-free male C57L/B6 mice and the Trichinella-infected mice were used to measure the score of abdominal withdrawal reflex (AWR). To compare molecular, biological and biochemical evidences of given probiotics with normal and positive control groups in mice, we conducted quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blotting, and cytokine analysis. RESULTS: Pi-IBS-induced immune response was confirmed that PAR-2 mRNA level was significantly increased by Trichinella infection (P < 0.05). The reduction of Pi-IBS symptoms through Trichinella infection and the effects of given probiotics were confirmed by a change in the protein levels of cytokines (P < 0.05). In addition, the administration of DW (Daewon) probiotics significantly decreased serum levels of IL-1 and IL-6 (P < 0.05). CONCLUSIONS: We have demonstrated that the given probiotics decreased pro-inflammatory cytokine levels in both the control and Pi-IBS induced mice. Taken all the results together, the results support that DW probiotics has a potential as a probiotic medication for patient with IBS via regulating TNF-α and IL-6 protein levels and serum IL-1 and IL-6 levels.


Assuntos
Síndrome do Intestino Irritável/tratamento farmacológico , Probióticos/administração & dosagem , Triquinelose/complicações , Animais , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/genética , Síndrome do Intestino Irritável/metabolismo , Lactobacillus/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor PAR-2/genética , Receptor PAR-2/metabolismo , Trichinella/fisiologia , Triquinelose/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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