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1.
PLoS One ; 15(4): e0222969, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32352958

RESUMO

In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36ß and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.


Assuntos
Comunicação Celular , Células Endoteliais/metabolismo , Interleucina-17/metabolismo , Interleucina-1/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Células Cultivadas , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
J Leukoc Biol ; 107(5): 783-796, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32125036

RESUMO

IL-37, a newly identified IL-1 family cytokine, has been shown to play an important role in inflammatory diseases, autoimmune diseases, and carcinogenesis. IL-37 has been suggested to suppress tumoral angiogenesis, whereas some publications showed that IL-37 promoted angiogenesis through TGF-ß signaling in both physiologic and pathologic conditions. Therefore, the function of IL-37 in tumoral angiogenesis is not clear and the underlying mechanism is not known. In this current study, we investigated the direct role of IL-37 on endothelial cells, as well as its indirect effect on angiogenesis through functioning on tumor cells both in vitro and in vivo. We found that IL-37 treatment directly promoted HUVEC migration and tubule formation, indicating IL-37 as a proangiogenic factor. Surprisingly, the supernatants from IL-37 overexpressing tumor cell line promoted HUVEC apoptosis and inhibited its migration and tubule formation. Furthermore, we demonstrated that IL-37 suppressed tumor angiogenesis in a murine orthotopic hepatocellular carcinoma model, suggesting its dominant antiangiogenesis role in vivo. Moreover, microarray and qPCR analysis demonstrated that IL-37 reduced the expressions of proangiogenic factors and increased the expressions of antiangiogenic factors by tumor cells. Matrix metalloproteinase (MMP)2 expression was significantly decreased by IL-37 in both cell lines and murine tumor models. MMP9 and vascular endothelial growth factor expressions were also reduced in murine tumors overexpressing IL-37, as well as in cell lines overexpressing IL-37 under hypoxic conditions. In conclusion, although IL-37 could exert direct proangiogenic effects on endothelial cells, it plays an antiangiogenic role via modulating proangiogenic and antiangiogenic factor expressions by tumor cells in the tumor microenvironment.


Assuntos
Inibidores da Angiogênese/metabolismo , Interleucina-1/metabolismo , Neovascularização Patológica/metabolismo , Microambiente Tumoral/imunologia , Inibidores da Angiogênese/farmacologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Interleucina-1/farmacologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/imunologia , Microambiente Tumoral/efeitos dos fármacos
3.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L137-L147, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159969

RESUMO

Neutrophil extracellular traps (NETs) provide host defense but can contribute to the pathobiology of diverse human diseases. We sought to determine the extent and mechanism by which NETs contribute to human airway cell inflammation. Primary normal human bronchial epithelial cells (HBEs) grown at air-liquid interface and wild-type (wt)CFBE41o- cells (expressing wtCFTR) were exposed to cell-free NETs from unrelated healthy volunteers for 18 h in vitro. Cytokines were measured in the apical supernatant by Luminex, and the effect on the HBE transcriptome was assessed by RNA sequencing. NETs consistently stimulated IL-8, TNF-α, and IL-1α secretion by HBEs from multiple donors, with variable effects on other cytokines (IL-6, G-CSF, and GM-CSF). Expression of HBE RNAs encoding IL-1 family cytokines, particularly IL-36 subfamily members, was increased in response to NETs. NET exposure in the presence of anakinra [recombinant human IL-1 receptor antagonist (rhIL-1RA)] dampened NET-induced changes in IL-8 and TNF-α proteins as well as IL-36α RNA. rhIL-36RA limited the increase in expression of proinflammatory cytokine RNAs in HBEs exposed to NETs. NETs selectively upregulate an IL-1 family cytokine response in HBEs, which enhances IL-8 production and is limited by rhIL-1RA. The present findings describe a unique mechanism by which NETs may contribute to inflammation in human lung disease in vivo. NET-driven IL-1 signaling may represent a novel target for modulating inflammation in diseases characterized by a substantial NET burden.


Assuntos
Brônquios/citologia , Células Epiteliais/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-1/metabolismo , Interleucina-8/metabolismo , Adulto , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Elastase de Leucócito/metabolismo , Peroxidase/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
4.
Ann Rheum Dis ; 79(4): 481-489, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32094158

RESUMO

OBJECTIVE: Syndecan-4 (sdc4) is a cell-anchored proteoglycan that consists of a transmembrane core protein and glucosaminoglycan (GAG) side chains. Binding of soluble factors to the GAG chains of sdc4 may result in the dimerisation of sdc4 and the initiation of downstream signalling cascades. However, the question of how sdc4 dimerisation and signalling affects the response of cells to inflammatory stimuli is unknown. METHODS: Sdc4 immunostaining was performed on rheumatoid arthritis (RA) tissue sections. Interleukin (IL)-1 induced extracellular signal-regulated kinases (ERK) phosphorylation and matrix metalloproteinase-3 production was investigated. Il-1 binding to sdc4 was investigated using immunoprecipitation. IL-1 receptor (IL1R1) staining on wild-type, sdc4 and IL1R1 knockout fibroblasts was performed in fluorescence-activated cell sorting analyses. A blocking sdc4 antibody was used to investigate sdc4 dimerisation, IL1R1 expression and the histological paw destruction in the human tumour necrosis factor-alpha transgenic mouse. RESULTS: We show that in fibroblasts, the loss of sdc4 or the antibody-mediated inhibition of sdc4 dimerisation reduces the cell surface expression of the IL-1R and regulates the sensitivity of fibroblasts to IL-1. We demonstrate that IL-1 directly binds to sdc4 and in an IL-1R-independent manner leads to its dimerisation. IL-1-induced dimerisation of sdc4 regulates caveolin vesicle-mediated trafficking of the IL1R1, which in turn determines the responsiveness to IL-1. Administration of antibodies (Ab) against the dimerisation domain of sdc4, thus, strongly reduces the expression IL1R1 on arthritic fibroblasts both in vitro and an animal model of human RA. CONCLUSION: Collectively, our data suggest that Ab that specifically inhibit sdc4 dimerisation may support anti-IL-1 strategies in diseases such as inflammatory arthritis.


Assuntos
Anticorpos Bloqueadores/farmacologia , Artrite Reumatoide/metabolismo , Receptores Tipo I de Interleucina-1/efeitos dos fármacos , Sindecana-4/antagonistas & inibidores , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Dimerização , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/metabolismo , Técnicas de Inativação de Genes , Heparitina Sulfato , Membro Posterior , Humanos , Interleucina-1/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Células NIH 3T3 , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Fosforilação/efeitos dos fármacos , Transporte Proteico , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais , Sindecana-4/genética , Sindecana-4/metabolismo , Membrana Sinovial/metabolismo , Fator de Necrose Tumoral alfa/genética
5.
Adv Immunol ; 145: 55-93, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32081200

RESUMO

The NLRP3 inflammasome is a cytoplasmic multiprotein complex, the assembly of which can be initiated in response to various exogenous or endogenous danger signals. Excessive activation of the NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human inflammatory diseases, suggesting that the NLRP3 inflammasome is a potential target for the treatment of these diseases. However, clinical drugs targeting the NLRP3 inflammasome are still not available. Recent data have elucidated the different signaling pathways or events that can control NLRP3 inflammasome activation and have provided some potential compounds with anti-NLRP3 inflammasome activity. Here, we summarize the molecular mechanisms and diseases involved in NLRP3 inflammasome activation and discuss the potential strategies targeting different aspects of the NLRP3 inflammasome and its implications for the treatment of inflammatory diseases.


Assuntos
Alarminas/metabolismo , Inflamassomos/antagonistas & inibidores , Inflamação/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Padrões Moleculares Associados a Patógenos/metabolismo , Transdução de Sinais/imunologia , Animais , Humanos , Inflamassomos/metabolismo , Inflamação/imunologia , Inflamação/patologia , Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo
6.
Adv Exp Med Biol ; 1240: 1-23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060884

RESUMO

Interleukin 1 (IL-1) has long been known for its pleiotropic effects on inflammation that plays a complex, and sometimes contrasting, role in different stages of cancer development. As a major proinflammatory cytokine, IL-1ß is mainly expressed by innate immune cells. IL-1α, however, is expressed by various cell types under physiological and pathological conditions. IL-1R1 is the main receptor for both ligands and is expressed by various cell types, including innate and adaptive immune cell types, epithelial cells, endothelial cells, adipocytes, chondrocytes, fibroblasts, etc. IL-1 and IL-1R1 receptor interaction leads to a set of common signaling pathways, mainly the NF-kB and MAP kinase pathways, as a result of complex positive and negative regulations. The variety of cell types with IL-1R1 expression dictates the role of IL-1 signaling at different stages of cancer, which under certain circumstances leads to contrasting roles in tumor development. Recent availability of IL-1R1 conditional knockout mouse model has made it possible to dissect the role of IL-1/IL-1R1 signaling transduction in different cell types within the tumor microenvironment. This chapter will focus on the role of IL-1/IL-1R1 in different cell types within the tumor microenvironment and discuss the potential of targeting this pathway in cancer therapy.


Assuntos
Interleucina-1/imunologia , Interleucina-1/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1/antagonistas & inibidores , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
7.
Adv Exp Med Biol ; 1240: 95-110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060891

RESUMO

The ability of the immune system to prevent or control the growth of tumor cells is critically dependent on inflammatory processes that lead to the activation, expansion, and recruitment of antitumor effector cells into the tumor microenvironment (TME). These processes are orchestrated by soluble cytokines produced in tissues that alarm local immune surveillance cells (such as dendritic cells, DCs) to mobilize protective antitumor immune populations (B cells, T cells). The interleukin (IL)-36 family of pro-inflammatory cytokines plays an important role in multiple disease processes, ranging from an instigator of autoimmune psoriasis to an initiator of therapeutic immune responses against tumor cells. This chapter will focus on the biologic role of immunomodulatory IL-36 family cytokines in the cancer setting and their potential utility in the design of effective interventional therapies. (127 words).


Assuntos
Interleucina-1/imunologia , Interleucina-1/metabolismo , Neoplasias/imunologia , Microambiente Tumoral , Animais , Células Dendríticas/imunologia , Humanos , Linfócitos T/imunologia
8.
Gene ; 737: 144445, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32035244

RESUMO

OBJECTIVE: The function of IL-37 in cancer remains largely unclear. The present research was to probe the protein expression of IL-37 and Oct4 in hepatocellular carcinoma (HCC), para-cancerous tissues (PT) and cancer cell lines, and discuss their relationship. METHODS: Forty-nine HCC specimens and forty-nine PT samples were collected for immunohistochemical staining of IL-37 and Oct4 protein. Then, the correlations among IL-37, Oct4 and the clinical indicators were analyzed. In further in vitro studies, IL-37 was over expressed in HepG2 and MHCC97H cancer cell lines by gene transfection using a lipo3000 kit. Finally, the protein expression of IL-37 and Oct4 was detected by immunofluorescence and western blot to verify the in vivo correlation between IL and 37 and Oct4. RESULTS: In HCC, IL-37 protein expression was weakly positive with a positive rate of 12.2% while Oct4 expression was strongly positive with a positive rate of 91.8%. In PT, strong positive IL-37 (83.7%) and weakly positive Oct4 (91.8%) were shown. The increased IL-37 and decreased Oct4 induced by IL-37 gene transfection were observed through IF in cells. In terms of clinical significance, the difference of IL-37 expression between HCC and PT was statistically significant (χ2 = 51.815, P = 3.2796 × 10-11). IL-37 in tumor tissues was associated with serum AFP (χ2 = 5.515, P = 0.048) and cirrhosis (χ2 = 7.451, P = 0.014). IL-37 expression of PT was link to gender (χ2 = 10.376, P = 0.013) and tumor size (χ2 = 8.118, P = 0.04). The expression of Oct4 in HCC was related to the patient's gender and cirrhosis. Importantly, there was a negative correlation between IL and 37 and Oct4 in tumor tissues (r = -0.299, P = 0.047) but not in PT (P > 0.05). Oct4 protein expression was down-regulated by IL-37 by 63.35% in HepG2 cells (P < 0.05) and 95.20% in MHCC97H cells (P < 0.05). CONCLUSION: IL-37 expression in tumor tissues and PT was related to serum AFP and liver cirrhosis, tumor size, respectively. IL-37 protein expression was correlated with Oct4 in cancer cell lines and tumor tissues but not PT. The present study indicated that IL-37 might play a role in the development of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Interleucina-1/metabolismo , Neoplasias Hepáticas/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
9.
BMC Cancer ; 20(1): 92, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013927

RESUMO

BACKGROUND AND AIMS: Colorectal cancer (CRC) is a major killer. Host immunity is important in tumorigenesis. Direct comparison among IL-36α, IL-36ß and IL-36γ in the prognosis of CRC is unclear. METHODS: CRC tissue arrays were generated from colorectostomy samples with TNM stage, invasion depth and the demography of these patients (n = 185). Using immunohistochemistry/histopathology, IL-36α, IL-36ß and IL-36γ were determined, in comparison to non-cancer tissues. RESULTS: A significant association was observed between colonic IL-36α, IL-36ß or IL-36γ and the presence of cancer (with all P < 0.0001). Using ROC curve analysis, specificity and sensitivity of IL-36α, IL-36ß or IL-36γ were confirmed, with area under the curve (AUC) values of 0.68, 0.73 and 0.65, respectively. Significant differences in survival were observed between IL-36αhigh and IL-36αlow (P = 0.003) or IL-36γhigh and IL-36γlow (P = 0.03). Survival curves varied significantly when further stratification into sub-groups, on the basis of combined levels of expression of two isotypes of IL-36 was undertaken. A significant difference was observed when levels of IL-36α and IL-36ß were combined (P = 0.01), or a combination of IL-36α plus IL-36γ (P = 0.002). The sub-groups with a combination of IL-36αhigh plus IL-36ßhigh, or IL-36αhigh plus IL-36γlow exhibited the longest survival time among CRC patients. In contrast, the sub-groups of IL-36αlow plus IL-36ßhigh or IL-36αlow plus IL-36γhigh had the shortest overall survival. Using the log-rank test, IL-36αhigh expression significantly improved survival in patients with an invasion depth of T4 (P < 0.0001), lymph node metastasis (P = 0.04), TNM III-IV (P = 0.03) or with a right-sided colon tumour (P = 0.02). Similarly, IL-36γlow expression was significantly associated with improved survival in patients with no lymph node metastasis (P = 0.008), TNM I-II (P = 0.03) or with a left-sided colon tumour (P = 0.05). Multivariate analysis demonstrated that among IL-36α, IL-36ß and IL-36γ, only IL-36α (HR, 0.37; 95% CI, 0.16-0.87; P = 0.02) was an independent factor in survival, using Cox proportional hazards regression analysis. CONCLUSION: IL-36α or IL-36γ are reliable biomarkers in predicting the prognosis of CRC during the later or early stages of the disease, respectively. Combining IL-36α plus IL-36γ appears to more accurately predict the postoperative prognosis of CRC patients. Our data may be useful in the management of CRC.


Assuntos
Neoplasias Colorretais/patologia , Interleucina-1/metabolismo , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos
10.
Sci Rep ; 10(1): 1718, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015355

RESUMO

To determine the association of opening the paravesical space in relation to its occurrence of de novo SUI in an animal model. Thirty five female Sprague Dawley rats were divided into 5 groups of 7 rats each: Control group, Sham groups(F, H), and Study groups(MF, MH). Groups labeled with "F" had the paravesical space opened, "H" had tissue dissection with no opening of the space, and "M" had mesh implanted inside the vaginal wall. Urodynamic studies, immunohistochemical analysis, and western blot were done at day 40. The mean weight and age of 35 rats were 302.1 ± 25.1 grams and 12.8 ± 1.2 weeks old. No significant differences were noted among the control, Sham F, Sham H, Study MF, and Study MH on the voiding pressure and voided volume. The Sham F and Study MF (opened paravesical space) groups had significantly lower values on leak point pressures (LPP) (p = 0.026; p < 0.001) and shorter voiding intervals (p = 0.032; p = 0.005) when compared to other groups. Immunohistochemical analysis showed IL-1 and TNF-α to be intensely increased for the Study MF group (p = 0.003; p = <0.001). MMP-2 and CD 31 markers were also significantly higher in the Study MH and MF group. NGF expression was significantly increased in the Study MF and Sham F groups. Thus, opening of the paravesical space causes an increased inflammatory reaction, which leads to tissue destruction and lower urinary tract dysfunction, exemplified in the study with low leak point pressure and shortened voiding intervals.


Assuntos
Inflamação/imunologia , Sintomas do Trato Urinário Inferior/imunologia , Prolapso de Órgão Pélvico/cirurgia , Pelve/anatomia & histologia , Uretra/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-1/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Fator de Crescimento Neural/metabolismo , Pelve/cirurgia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Uretra/patologia , Urodinâmica , Procedimentos Cirúrgicos Urogenitais
11.
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
12.
Biomed Pharmacother ; 122: 109705, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918276

RESUMO

IL-37 was discovered as an anti-inflammatory and immunosuppressive cytokine of the IL-1 family. Significant advancements in the understanding of signaling pathways associated with IL-37 have been made in recent years. IL-37 binds to IL-18R and recruits IL-1R8 to form the IL-37/IL-1R8/IL-18Rα complex. Capase-1 plays a key role in the nuclear transduction of IL-37 signal, processing precursor IL-37 into the mature isoform, and interacting with Smad3. IL-37 exerts its role by activating anti-inflammation pathways including AMPK, PTEN, Mer, STAT3 and p62, and promoting tolerogenic dendritic cells and Tregs. In addition, IL-37 inhibits pro-inflammatory cytokines such as IL-1, IL-6, IL-8, IL-17, IL-23, TNF-α, and IFN-γ, and suppresses Fyn, MAPK, TAK1, NFκB, and mTOR signaling. The final effects of IL-37 depend on the interaction among IL-18R, IL-1R8, IL-37 and IL-18BP. Previous studies have deciphered the role of IL-37 in the development and pathogenesis of autoimmune diseases, chronic infections and cancer. In this review, we discuss the role of IL-37 in psoriasis, atopic dermatitis, Behcet's diseases, systemic lupus erythematosus, and other skin and connective tissue diseases.


Assuntos
Doenças do Tecido Conjuntivo/metabolismo , Interleucina-1/metabolismo , Dermatopatias/metabolismo , Pele/metabolismo , Animais , Doenças Autoimunes/metabolismo , Citocinas/metabolismo , Humanos
13.
Clin Exp Immunol ; 199(3): 303-313, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31758701

RESUMO

Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40-80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. LCWE-injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE-injected mice developed cardiac ganglion inflammation, that may affect the impulse-conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE-injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)-1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1-/- mice and in wild-type mice treated with anakinra. Thus, similar to clinical KD, the LCWE-induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL-1 signaling. These data support the acceleration of anti-IL-1 therapy trials to benefit KD patients.


Assuntos
Modelos Animais de Doenças , Interleucina-1/metabolismo , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Vasculite/fisiopatologia , Animais , Antirreumáticos/farmacologia , Produtos Biológicos/toxicidade , Parede Celular/química , Criança , Eletrocardiografia/efeitos dos fármacos , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1/genética , Lactobacillus casei/química , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Linfonodos Mucocutâneos/induzido quimicamente , Síndrome de Linfonodos Mucocutâneos/terapia , Fator de Crescimento Neural/sangue , Receptores Tipo I de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasculite/induzido quimicamente , Vasculite/terapia
14.
Prostate ; 80(2): 133-145, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31730277

RESUMO

BACKGROUND: The androgen receptor (AR) nuclear transcription factor is a therapeutic target for prostate cancer (PCa). Unfortunately, patients can develop resistance to AR-targeted therapies and progress to lethal disease, underscoring the importance of understanding the molecular mechanisms that underlie treatment resistance. Inflammation is implicated in PCa initiation and progression and we have previously reported that the inflammatory cytokine, interleukin-1 (IL-1), represses AR messenger RNA (mRNA) levels and activity in AR-positive (AR+ ) PCa cell lines concomitant with the upregulation of prosurvival biomolecules. Thus, we contend that IL-1 can select for AR-independent, treatment-resistant PCa cells. METHODS: To begin to explore how IL-1 signaling leads to the repression of AR mRNA levels, we performed comprehensive pathway analysis on our RNA sequencing data from IL-1-treated LNCaP PCa cells. Our pathway analysis predicted nuclear factor kappa B (NF-κB) p65 subunit (RELA), a canonical IL-1 signal transducer, to be significantly active and potentially regulate many genes, including AR. We used small interfering RNA (siRNA) to silence the NF-κB family of transcription factor subunits, RELA, RELB, c-REL, NFKB1, or NFKB2, in IL-1-treated LNCaP, C4-2, and C4-2B PCa cell lines. C4-2 and C4-2B cell lines are castration-resistant LNCaP sublines and represent progression toward metastatic PCa disease, and we have previously shown that IL-1 represses AR mRNA levels in C4-2 and C4-2B cells. RESULTS: siRNA revealed that RELA alone is sufficient to mediate IL-1 repression of AR mRNA and AR activity. Intriguingly, while LNCaP cells are more sensitive to IL-1-mediated repression of AR than C4-2 and C4-2B cells, RELA siRNA led to a more striking derepression of AR mRNA levels and AR activity in C4-2 and C4-2B cells than in LNCaP cells. CONCLUSIONS: These data indicate that there are RELA-independent mechanisms that regulate IL-1-mediated AR repression in LNCaP cells and suggest that the switch to RELA-dependent IL-1 repression of AR in C4-2 and C4-2B cells reflects changes in epigenetic and transcriptional programs that evolve during PCa disease progression.


Assuntos
Interleucina-1/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Fator de Transcrição RelA/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-1alfa/farmacologia , Masculino , NF-kappa B/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores Androgênicos/genética , Fator de Transcrição RelA/genética
15.
J Plast Reconstr Aesthet Surg ; 73(3): 590-597, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31734236

RESUMO

OBJECTIVE: This study used an experimental model mimicking early postoperative enteral feeding after the transfer of free jejunal flap and tested the hypothesis that jejunal infusion with dextrose or saline is associated with improved tissue perfusion and/or less mucosal damage after ischemia/reperfusion (IR) injury. METHODS: Thirty-five male Sprague Dawley rats were randomly divided into five groups: sham group (no IR and no intraluminal infusion); IR control group (IR but not intraluminal infusion); IR plus intraluminal 0.9% NaCl infusion or 5% dextrose or 10% dextrose infusion groups. A jejunal segment of each rat was isolated. The animals had jejunal ischemia for 40 min, reperfusion, and intestinal infusion on the basis of their allocation. Jejunal tissue perfusion was measured with laser Doppler flowmetry at one hour and two hours after reperfusion, after which the animals were sacrificed and tissue samples were obtained for the scoring of histological damage at superficial and cryptic epithelium, villus structure, and inflammatory cell infiltration and tissue nitric oxide (NO), interleukin (IL)-1, IL-6, and matrix metalloproteinase-1 (MMP) level measurements. RESULTS: At 1 h of reperfusion, IR plus 5% dextrose and 10% dextrose groups both had significantly higher perfusion rates than the IR control group (384.8 ± 26.7 and 462.4 ± 44.7 versus 270.3 ± 34.2 PU, respectively, p < 0.05 for both). These differences were maintained at 2 h of reperfusion (p < 0.05 for both). Saline infusion, however, resulted in improved tissue perfusion only at the early phase of reperfusion. Intraluminal infusion with dextrose solution, either 5% or 10%, was associated with higher tissue NO, IL-1, and IL-6 levels than that in the sham group (p < 0.05 for all). In addition, intraluminal infusion of any fluid resulted in less severe histological damage (8.1 ± 0.9 versus 5.8 ± 1.0, 5.4 ± 0.9, and 5.2 ± 1.9, for IR plus saline, 5% dextrose and 10% dextrose groups, respectively, p < 0.05 for all). CONCLUSIONS: Intraluminal infusion of fluids, particularly dextrose solutions, may be protective against IR injury as demonstrated by improved tissue perfusion and less histological damage. In addition, increases in tissue NO, IL-1, and IL-6 levels in association with dextrose infusion may be explained by the activation of pro-inflammatory and anti-inflammatory protective pathways. These support early enteral feeding after free jejunum flap transfers; however, further studies are warranted.


Assuntos
Jejuno/cirurgia , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Retalhos de Tecido Biológico/cirurgia , Glucose/farmacologia , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/patologia , Jejuno/irrigação sanguínea , Jejuno/metabolismo , Jejuno/patologia , Fluxometria por Laser-Doppler , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Reperfusão/métodos , Traumatismo por Reperfusão/patologia
16.
J Leukoc Biol ; 107(3): 379-391, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31608507

RESUMO

Inflammasomes are a specialized group of intracellular sensors that are key components of the host innate immune system. Autoinflammatory diseases are disorders of the innate immune system that are characterized by recurrent inflammation and serious complications. Dysregulation of the inflammasome is associated with the onset and progression of several autoinflammatory and autoimmune diseases, including cryopyrin-associated periodic fever syndrome, familial Mediterranean fever, rheumatoid arthritis, and systemic lupus erythematosus. In this review, we discuss the involvement of various inflammasome components in the regulation of autoinflammatory disorders and describe the manifestations of these autoinflammatory diseases caused by inflammasome activation.


Assuntos
Doenças Autoimunes/fisiopatologia , Inflamassomos/metabolismo , Inflamação/fisiopatologia , Humanos , Interleucina-1/metabolismo , Modelos Biológicos , Síndrome
17.
Acta Odontol Scand ; 78(2): 126-131, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31570027

RESUMO

Objectives: This study aimed to investigate whether Epstein-Barr virus (EBV) positive periapical lesions exhibited higher mRNA levels of Notch signalling molecules (Notch2 and Jagged1), bone resorption regulators (receptor activator of nuclear factor kappa-ß ligand (RANKL) and osteoprotegerin (OPG)), and proinflammatory cytokines (tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and IL-6) compared to EBV negative lesions. Additionally, the potential correlation between investigated molecules in periapical lesions was analyzed.Materials and methods: Sixty-four apical periodontitis lesions were obtained subsequent to standard apicoectomy procedure. The presence of EBV was determined using nested PCR. Based on the presence of EBV all periapical lesions were divided into two groups, 29 EBV positive and 35 EBV negative lesions. A reverse transcriptase real-time PCR was used to determine mRNA levels of Notch2, Jagged1, RANKL, OPG, TNF-α, IL-1ß and IL-6.Results: Significantly higher mRNA levels of Notch2, Jagged1, RANKL and IL-1ß were observed in EBV positive compared to EBV negative lesions. Significant positive correlation was present between Notch2 and Jagged1, Jagged1 and RANKL, and IL-ß and TNF-α in EBV positive periapical lesions.Conclusions: Notch signalling pathway may be involved in alveolar bone resorption in apical periodontitis lesions infected by EBV.


Assuntos
Reabsorção Óssea , Infecções por Vírus Epstein-Barr , Proteína Jagged-1 , Periodontite Periapical , Receptor Notch2 , Reabsorção Óssea/virologia , Citocinas , Herpesvirus Humano 4 , Humanos , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Proteína Jagged-1/metabolismo , Osteoprotegerina , Periodontite Periapical/metabolismo , Periodontite Periapical/virologia , Ligante RANK/metabolismo , Receptor Notch2/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
18.
J Infect Dis ; 221(6): 983-988, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31586390

RESUMO

In recent studies, the interleukin (IL)-36 cytokines were shown to be elevated in women with non-Lactobacillus-dominated vaginal microbiomes. In this study, we evaluated IL36G expression in clinical samples from women with and without bacterial vaginosis (BV) and a human 3-dimensional cervical epithelial cell model. IL36G expression was significantly elevated in cervicovaginal epithelial cells isolated from BV-positive women and corresponded with increased neutrophil counts relative to BV-negative women. In addition, specific BV-associated bacterial species as well as a polymicrobial cocktail significantly induced IL36G expression in vitro. These findings suggest that IL-36γ may exhibit an important function in the host response to BV and other sexually transmitted infections.


Assuntos
Células Epiteliais/metabolismo , Interleucina-1/metabolismo , Vaginose Bacteriana/metabolismo , Adulto , Bactérias , Células Cultivadas , Colo do Útero , Células Epiteliais/microbiologia , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-1/genética , Neutrófilos , Vagina/citologia , Adulto Jovem
19.
Int Rev Immunol ; 39(1): 3-10, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31633447

RESUMO

Interleukin-37 (IL-37) is a newly introduced cytokine to interleukin-1 family. Many studies have demonstrated that IL-37 owns immunosuppressive effects against both innate and acquired immune responses via inhibition of several inflammatory mediators. Thence, IL-37 has anti-inflammatory action in some diseases including cancer, autoimmune diseases, cardiovascular diseases and infectious diseases. Recent investigations have reported the important role of IL-37 in immunity against viral, bacterial and fungal infections as they prevent inappropriate immune activation and suppress the inflammation induced by these infectious agents. Thus, IL-37 could play a crucial role in protecting host tissues from injury during infections by damping excessive inflammatory reactions. However, the precise roles of IL-37 in infectious diseases remain largely unknown. The current review shed light on the pivotal role of IL-37 in infectious diseases such as the human immunodeficiency virus-1 (HIV-1), viral myocarditis, hepatitis C virus (HCV), hepatitis B virus (HBV), tuberculosis, leprosy, pneumococcal pneumonia, listeria infection, aspergillosis, candidiasis and eumycetoma. In conclusion, this review reported that IL-37 has a crucial role in reducing infection-associated inflammation and has a good impact on inflammation-induced pathology. However, tight regulation that achieved balance between effector immune responses that required for pathogen elimination and limited tissue damage that resulted from excessive inflammation should be existed in the potential IL-37 therapy to prevent clinical complications of a disease.


Assuntos
Infecções Bacterianas/imunologia , Inflamação/imunologia , Interleucina-1/imunologia , Micoses/imunologia , Viroses/imunologia , Animais , Infecções Bacterianas/metabolismo , Infecções Bacterianas/microbiologia , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/genética , Inflamação/metabolismo , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1/genética , Interleucina-1/metabolismo , Micoses/metabolismo , Micoses/microbiologia , Viroses/metabolismo , Viroses/virologia
20.
Rheumatology (Oxford) ; 59(4): 828-838, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504934

RESUMO

OBJECTIVES: IL-36 agonists are pro-inflammatory cytokines involved in the pathogenesis of psoriasis. However, their role in the pathogenesis of arthritis and treatment response to DMARDs in PsA remains uncertain. Therefore, we investigated the IL-36 axis in the synovium of early, treatment-naïve PsA, and for comparison RA patients, pre- and post-DMARDs therapy. METHODS: Synovial tissues were collected by US-guided biopsy from patients with early, treatment-naïve PsA and RA at baseline and 6 months after DMARDs therapy. IL-36 family members were investigated in synovium by RNA sequencing and immunohistochemistry, and expression levels correlated with DMARDs treatment response ex vivo. Additionally, DMARDs effects on IL-36 were investigated in vitro in fibroblast-like synoviocytes. RESULTS: PsA synovium displayed a reduced expression of IL-36 antagonists, while IL-36 agonists were comparable between PsA and RA. Additionally, neutrophil-related molecules, which drive a higher activation of the IL-36 pathway, were upregulated in PsA compared with RA. At baseline, the synovial expression of IL-36α was significantly higher in PsA non-responders to DMARDs treatment, with the differential expression being sustained at 6 months post-treatment. In vitro, primary PsA-derived fibroblasts were more responsive to IL-36 stimulation compared with RA and, importantly, DMARDs treatment increased IL-36 expression in PsA fibroblasts. CONCLUSION: The impaired balance between IL-36 agonists-antagonists described herein for the first time in PsA synovium and the decreased sensitivity to DMARDs in vitro may explain the apparent lower efficacy of DMARDs in PsA compared with RA. Exogenous replacement of IL-36 antagonists may be a novel promising therapeutic target for PsA patients.


Assuntos
Artrite Psoriásica/imunologia , Expressão Gênica , Inflamação/imunologia , Membrana Sinovial/imunologia , Sinoviócitos/imunologia , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/genética , Artrite Psoriásica/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Biópsia , Humanos , Técnicas In Vitro , Inflamação/genética , Inflamação/metabolismo , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-1/metabolismo , Interleucinas/genética , Interleucinas/imunologia , Interleucinas/metabolismo , RNA Mensageiro/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo
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