Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 650
Filtrar
1.
Clin Oral Investig ; 24(1): 343-350, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31102041

RESUMO

OBJECTIVES: The aim of this study was to investigate in vitro the effect of clodronate on interleukin-1ß (IL-1ß)-stimulated human periodontal ligament fibroblasts (HPdLFs) with the focus on inflammatory factors of orthodontic tooth movement with and without compressive force. MATERIALS AND METHODS: HPdLFs were incubated with 5 µM clodronate and 10 ng/mL IL-1ß. After 48 h, cells were exposed to 3 h of compressive force using a centrifuge. The gene expression of cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), matrix metalloproteinase 8 (MMP-8), and the tissue inhibitor of MMP (TIMP-1) was analyzed using RT-PCR. Prostaglandin E2 (PGE-2), IL-6, and TIMP-1 protein syntheses were quantified via ELISA. RESULTS: Compressive force and IL-1ß induced an overexpression of COX-2 gene expression (61.8-fold; p < 0.05 compared with control), diminished by clodronate (41.1-fold; p < 0.05 compared with control). Clodronate slowed down the compression and IL-1ß induced IL-6 gene expression (161-fold vs. 85.6-fold; p < 0.05 compared with control). TNF-α was only slightly affected without statistical significance. Clodronate reduced IL-1ß-stimulated MMP-8 expression with and without compressive force. TIMP-1 on gene and protein level was downregulated in all groups. Analyzing the MMP-8/TIMP-1 ratio, the highest ratio was detected in IL-1ß-stimulated HPdLFs with compressive force (21.2-fold; p < 0.05 compared with control). Clodronate diminished IL-1ß-induced upregulation of MMP-8/TIMP-1 ratio with (11.5-fold; p < 0.05 compared with control) and without (12.5-fold; p < 0.05 compared with control) compressive force. CONCLUSION: Our study demonstrates a slightly anti-inflammatory effect by clodronate under compressive force in vitro. Additionally, the periodontal remodeling presented by the MMP-8/TIMP-1 ratio seems to be diminished by clodronate. CLINICAL RELEVANCE: Reduction of pro-inflammatory factors and reduction of periodontal remodeling might explain reduced orthodontic tooth movement under clodronate intake.


Assuntos
Ácido Clodrônico , Interleucina-1beta , Ligamento Periodontal , Fenômenos Biomecânicos , Células Cultivadas , Ácido Clodrônico/farmacologia , Dinoprostona , Fibroblastos , Humanos , Interleucina-1beta/fisiologia , Metaloproteinase 8 da Matriz/metabolismo , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Técnicas de Movimentação Dentária
2.
Endocr J ; 66(8): 691-699, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31105125

RESUMO

The cyclooxygenase2 (COX-2) enzyme catalyzes the first step of prostanoid biosynthesis, and is known for its crucial role in the pathogenesis of several inflammatory diseases including type 2 diabetes mellitus (T2DM). Although a variety of studies revealed that COX-2 played a role in the IL-1ß induced ß cell dysfunction, the molecular mechanism remains unclear. Here, using a cDNA microarray and in silico analysis, we demonstrated that inflammatory responses were upregulated in human T2DM islets compared with non-diabetic (ND) islets. COX-2 expression was significantly enhanced in human T2DM islets, correlated with the high inflammation level. PGE2, the catalytic product of COX-2, downregulated the functional gene expression of PDX1, NKX6.1, and MAFA and blunted the glucose induced insulin secretion of human islets. Conversely, inhibition of COX-2 activity by a pharmaceutical inhibitor prevented the ß-cell dysfunction induced by IL-1ß. COX-2 inhibitor also abrogated the IL-1ß autostimulation in ß cells, which further resulted in reduced COX-2 expression in ß cells. Together, our results revealed that COX-2/PGE2 signaling was involved in the regulation of IL-1ß autostimulation, thus forming an IL-1ß/COX-2/PGE2 pathway loop, which may result in the high inflammation level in human T2DM islets and the inflammatory impairment of ß cells. Breaking this IL-1ß/COX-2/PGE2 pathway loop provides a potential therapeutic strategy to improve ß cell function in the treatment of T2DM patients.


Assuntos
Ciclo-Oxigenase 2/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Dinoprostona/fisiologia , Interleucina-1beta/fisiologia , Ilhotas Pancreáticas/fisiopatologia , Adulto , Animais , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Dinoprostona/metabolismo , Retroalimentação Fisiológica/fisiologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Transdução de Sinais/fisiologia
3.
PLoS Pathog ; 15(4): e1007689, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30964929

RESUMO

NOD-like receptor protein 3 (NLRP3) inflammasome activation triggers caspase-1 activation-induced maturation of interleukin (IL)-1ß and IL-18 and therefore is important for the development of the host defense against various RNA viral diseases. However, the implication of this protein complex in human metapneumovirus (HMPV) disease has not been fully studied. Herein, we report that NLRP3 inflammasome plays a detrimental role during HMPV infection because NLRP3 inflammasome inhibition protected mice from mortality and reduced weight loss and inflammation without impacting viral replication. We also demonstrate that NLRP3 inflammasome exerts its deleterious effect via IL-1ß production since we observed reduced mortality, weight loss and inflammation in IL-1ß-deficient (IL-1ß-/-) mice, as compared to wild-type animals during HMPV infection. Moreover, the effect on these evaluated parameters was not different in IL-1ß-/- and wild-type mice treated with an NLRP3 inflammasome inhibitor. The production of IL-1ß was also abrogated in bone marrow derived macrophages deficient for NLRP3. Finally, we show that small hydrophobic protein-deleted recombinant HMPV (HMPV ΔSH) failed to activate caspase-1, which is responsible for IL-1ß cleavage and maturation. Furthermore, HMPV ΔSH-infected mice had less weight loss, showed no mortality and reduced inflammation, as compared to wild-type HMPV-infected mice. Thus, NLRP3 inflammasome activation seems to be triggered by HMPV SH protein in HMPV disease. In summary, once activated by the HMPV SH protein, NLRP3 inflammasome promotes the maturation of IL-1ß, which exacerbates HMPV-induced inflammation. Therefore, the blockade of IL-1ß production by using NLRP3 inflammasome inhibitors might be a novel potential strategy for the therapy and prevention of HMPV infection.


Assuntos
Inflamassomos/imunologia , Inflamação/imunologia , Interleucina-1beta/fisiologia , Metapneumovirus/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Infecções por Paramyxoviridae/imunologia , Proteínas Oncogênicas de Retroviridae/metabolismo , Animais , Feminino , Humanos , Inflamassomos/metabolismo , Inflamação/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Infecções por Paramyxoviridae/virologia , Proteínas Recombinantes/metabolismo , Proteínas Oncogênicas de Retroviridae/imunologia , Transdução de Sinais , Replicação Viral
4.
PLoS Pathog ; 15(2): e1007593, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30811485

RESUMO

Hepatitis C virus (HCV) infection remains a major cause of hepatic inflammation and liver disease. HCV triggers NLRP3 inflammasome activation and interleukin-1ß (IL-1ß) production from hepatic macrophages, or Kupffer cells, to drive the hepatic inflammatory response. Here we examined HCV activation of the NLRP3 inflammasome signaling cascade in primary human monocyte derived macrophages and THP-1 cell models of hepatic macrophages to define the HCV-specific agonist and cellular processes of inflammasome activation. We identified the HCV core protein as a virion-specific factor of inflammasome activation. The core protein was both necessary and sufficient for IL-1ß production from macrophages exposed to HCV or soluble core protein alone. NLRP3 inflammasome activation by the HCV core protein required calcium mobilization linked with phospholipase-C activation. Our findings reveal a molecular basis of hepatic inflammasome activation and IL-1ß release triggered by HCV core protein.


Assuntos
Sinalização do Cálcio/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas do Core Viral/fisiologia , Cálcio/metabolismo , Proteínas de Transporte , Hepacivirus/metabolismo , Hepacivirus/patogenicidade , Hepatite C , Humanos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/fisiologia , Macrófagos do Fígado , Fígado , Hepatopatias , Macrófagos/metabolismo , NF-kappa B , Cultura Primária de Células , Espécies Reativas de Oxigênio , Células THP-1/metabolismo , Fosfolipases Tipo C/metabolismo , Proteínas do Core Viral/metabolismo
5.
Brain Behav Immun ; 75: 129-136, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30261304

RESUMO

Interleukin-1 beta (IL-1ß) is a cytokine mediator of perinatal brain injury. The effect of sub-chronic systemic IL-1ß exposure in perinatal and offspring outcomes is unclear. The aim of this study was to examine the effects of maternal IL-1ß exposure on pregnancy and offspring outcomes. At E15, CD1 dams were allocated to receive intraperitoneal injection of phosphate buffered saline or mouse recombinant IL-1ß (1 mcg) for four consecutive days. We analyzed pup survivaland neurobehavioral status. At E18, placental H&E staining and fetal brain Nissl staining was performed. Placental gene expression was analyzed by qPCR and T cell infiltration was analyzed by flow cytometry. Effects of inflammation on feto-placental blood flow were analyzed by Doppler ultrasonography. IL-1ß decreased pup survival (P < .0001) and adversely affected offspring performance on neurodevelopmental tests (P < .05). Placentas of exposed dams exhibited significant thinning of maternal and fetal sides, and fetal brain exhibited cortical thinning. Placental qPCR analysis revealed significant upregulation of NFκB2 (P = .0021) and CXCL11 (P = .0401). While maternal IL-1ß exposure did not affect feto-placental blood flow, placental flow cytometry showed an increase in placental infiltration of CD4+ T cells at 24 h post-injection (hpi, P < .0001) and CD8+ T cells at 72 hpi (P = .0217). Maternal sub-chronic, systemic inflammation with IL-1ß decreased pup survival and played a key role in perinatal brain injury. The mechanisms behind these outcomes may involve immune system activation and alterations in placental T cell trafficking.


Assuntos
Interleucina-1beta/efeitos adversos , Placenta/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Animais , Lesões Encefálicas/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Feminino , Feto/metabolismo , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/fisiologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Gravidez
6.
Biochem Pharmacol ; 157: 202-209, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30195729

RESUMO

The search for novel therapies for the treatment of Alzheimer's disease is an urgent need, due to the current paucity of available pharmacological tools and the recent failures obtained in clinical trials. Among other strategies, the modulation of amyloid-triggered neuroinflammation by the endocannabinoid system seems of relevance. Previous data indicate that the enhancement of the endocannabinoid tone through the inhibition of the enzymes responsible for the degradation of their main endogenous ligands may render beneficial effects. Based on previously reported data, in which we described a paradoxical effect of the genetic deletion of the fatty acid amide hydrolase, we here aimed to expand our knowledge on the role of the endocannabinoid system in the context of Alzheimer's disease. To that end, we inhibited the production of interleukin-1ß, one of the main inflammatory cytokines involved in the neuroinflammation triggered by amyloid peptides, in a transgenic mouse model of this disease by using minocycline, a drug known to impair the synthesis of this cytokine. Our data suggest that interleukin-1ß may be instrumental in order to achieve the beneficial effects derived of fatty acid amide hydrolase genetic inactivation. This could be appreciated at the molecular (cytokine expression, amyloid production, plaque deposition) as well as behavioral levels (memory impairment). We here describe a previously unknown link between the endocannabinoid system and interleukin-1ß in the context of Alzheimer's disease that open new possibilities for the development of novel therapeutics.


Assuntos
Doença de Alzheimer/metabolismo , Amidoidrolases/genética , Interleucina-1beta/fisiologia , Doença de Alzheimer/genética , Animais , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Microglia/citologia , Minociclina/farmacologia , Fenótipo
7.
Mol Med ; 24(1): 45, 2018 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157748

RESUMO

BACKGROUND: Endothelial barrier dysfunction characterized by hyperpermeability of the vascular endothelium is a key factor in the pathogenesis of chronic inflammatory diseases and affects clinical outcomes. In states of chronic inflammation, mediators secreted by activated immune cells or vascular endothelium may affect the barrier function and permeability of the vascular endothelium. The matricellular R-spondin family member RSPO3 is produced by inflammatory-activated human monocytes and vascular endothelial cells, but its effects in the regulation of vascular endothelial barrier function remains elusive. METHODS: The present study investigates the effects of RSPO3 on the barrier function of adult human primary macro- and micro- vascular endothelial monolayers. Tight monolayers of primary endothelial cells from human coronary and pulmonary arteries, and cardiac, brain, and dermal microvascular beds were treated with RSPO3 either alone or in combination with pro-inflammatory mediator IL-1ß. Endothelial barrier function was assessed non-invasively in real-time using Electric Cell-substrate Impedance Sensing. RESULTS: RSPO3 treatment critically affected barrier function by enhancing the permeability of all vascular endothelial monolayers investigated. To confer hyperpermeable phenotype in vascular endothelial monolayers, RSPO3 induced inter-endothelial gap formation by disrupting the ß-catenin and VE-cadherin alignment at adherens junctions. RSPO3 synergistically enhanced the barrier impairing properties of the pro-inflammatory mediator IL-1ß. CONCLUSION: Here, we show that the matricellular protein RSPO3 is a mediator of endothelial hyperpermeability that can act in synergy with the inflammatory mediator IL-1ß. This finding stimulates further studies to delineate the endothelial barrier impairing properties of RSPO3 and its synergistic interaction with IL-1ß in chronic inflammatory diseases.


Assuntos
Permeabilidade Capilar , Endotélio Vascular/fisiologia , Interleucina-1beta/fisiologia , Trombospondinas/fisiologia , Linhagem Celular , Vasos Coronários/citologia , Células Endoteliais/fisiologia , Humanos , Microvasos/citologia , Artéria Pulmonar/citologia
8.
Neurobiol Learn Mem ; 155: 231-238, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30092312

RESUMO

Long (D2L) and Short (D2S) isoforms of D2 dopamine receptor differ in their biochemical and physiological properties, which could affect functioning of prefrontal cortex. Contribution of distinct D2 dopamine receptor isoforms to cognitive dysfunctions and its developmental regulation are currently not fully elucidated. In the present study, we evaluated developmental mRNA expression of D2S/D2L dopamine receptor isoforms within the rat medial prefrontal cortex (mPFC) in the model of neurodevelopmental cognitive dysfunction. Working memory performance (Y-maze spontaneous alternations) and D2S/D2L mRNA expression in the mPFC (by qRT-PCR) were evaluated in juvenile (P27), adolescent (P42-47) and adult (P75-90) rats after chronic early life treatment with proinflammatory cytokine interleukin (IL)-1ß (1 µg/kg i.p. daily P15-21). It was shown that IL-1ß elevation during the 3rd week of life leads to working memory deficit originating in juvenile animals and persisting into adulthood. D2S mRNA expression was strongly downregulated during adolescence, and such downregulation was exaggerated in animals injected with IL-1ß during P15-21. Early life IL-1ß administrations influenced developmental changes in the D2S/D2L mRNA ratio. This measure was found to be decreased in adolescent and adult control (intact and vehicle-treated) rats compared to juvenile control, while in the case of IL-1ß-treated animals, the decrease in D2S/D2L ratio was observed only in adulthood but not in adolescence compared to juvenile rats. During the adolescence, D2S mRNA expression was downregulated and D2S/D2L ratio was upregulated in the mPFC of rats treated with IL-1ß during the 3rd week of life compared to controls. Based on these data we conclude that changes in the developmental expression of D2 dopamine receptor splice variants within mPFC may underlie long-lasting cognitive deficit associated with neonatal pathology.


Assuntos
Encefalite/induzido quimicamente , Interleucina-1beta/administração & dosagem , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Modelos Animais de Doenças , Interleucina-1beta/fisiologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Córtex Pré-Frontal/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ratos Wistar
9.
Psychoneuroendocrinology ; 98: 95-100, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30121550

RESUMO

The science of neuroimmunopsychiatry has evolved rapidly in the last few years with the hope of tackling the unmet need in mood disorders. This article focuses on an inflammatory pathway, highly conserved in myeloid cells that may play a role in neuroinflammatory disorders including depression. Within the brain tissue, microglia are the myeloid cells that express the P2X7 ion channel that is connected through the NLRP3 inflammasome complex leading to release of IL-1ß and IL-18. We present, in the way of reviewing relevant literature, the preclinical data and scientific rationale supporting the role of the P2X7-NLRP3-IL-1ß pathway in mood disorders. We also highlight recent advances in drug discovery and development of P2X7 small molecule antagonists and P2X7 PET ligands which provide optimism that clinical tools are availableto address critical proof-of-concept experiments in mood disorders.


Assuntos
Transtornos do Humor/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Receptores Purinérgicos P2X7/fisiologia , Animais , Depressão/tratamento farmacológico , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/fisiologia , Microglia , Transtornos do Humor/fisiopatologia , Células Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Neuroimunomodulação/fisiologia , Antagonistas do Receptor Purinérgico P2X/metabolismo , Antagonistas do Receptor Purinérgico P2X/uso terapêutico
11.
J Orthop Res ; 36(11): 2901-2910, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29809295

RESUMO

Tissue engineering is a promising approach for the repair of articular cartilage defects, with engineered constructs emerging that match native tissue properties. However, the inflammatory environment of the damaged joint might compromise outcomes, and this may be impacted by the choice of cell source in terms of their ability to operate anabolically in an inflamed environment. Here, we compared the response of engineered cartilage derived from native chondrocytes and mesenchymal stem cells (MSCs) to challenge by TNFα and IL-1ß in order to determine if either cell type possessed an inherent advantage. Compositional (extracellular matrix) and functional (mechanical) characteristics, as well as the release of catabolic mediators (matrix metalloproteinases [MMPs], nitric oxide [NO]) were assessed to determine cell- and tissue-level changes following exposure to IL-1ß or TNF-α. Results demonstrated that MSC-derived constructs were more sensitive to inflammatory mediators than chondrocyte-derived constructs, exhibiting a greater loss of proteoglycans and functional properties at lower cytokine concentrations. While MSCs and chondrocytes both have the capacity to form functional engineered cartilage in vitro, this study suggests that the presence of an inflammatory environment is more likely to impair the in vivo success of MSC-derived cartilage repair. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2901-2910, 2018.


Assuntos
Condrócitos/fisiologia , Interleucina-1beta/fisiologia , Células-Tronco Mesenquimais/fisiologia , Engenharia Tecidual , Fator de Necrose Tumoral alfa/fisiologia , Animais , Bovinos , Glicosaminoglicanos/metabolismo , Metaloproteinases da Matriz/metabolismo , Óxido Nítrico/metabolismo
12.
Nat Commun ; 9(1): 1779, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725003

RESUMO

Mutations in Wiskott-Aldrich syndrome protein (WASP) cause autoimmune sequelae including colitis. Yet, how WASP mediates mucosal homeostasis is not fully understood. Here we show that WASP-mediated regulation of anti-inflammatory macrophages is critical for mucosal homeostasis and immune tolerance. The generation and function of anti-inflammatory macrophages are defective in both human and mice in the absence of WASP. Expression of WASP specifically in macrophages, but not in dendritic cells, is critical for regulation of colitis development. Importantly, transfer of WT anti-inflammatory macrophages prevents the development of colitis. DOCK8-deficient macrophages phenocopy the altered macrophage properties associated with WASP deficiency. Mechanistically, we show that both WASP and DOCK8 regulates macrophage function by modulating IL-10-dependent STAT3 phosphorylation. Overall, our study indicates that anti-inflammatory macrophage function and mucosal immune tolerance require both WASP and DOCK8, and that IL-10 signalling modulates a WASP-DOCK8 complex.


Assuntos
Colite/imunologia , Homeostase , Inflamação/imunologia , Interleucina-10/fisiologia , Mucosa Intestinal/metabolismo , Macrófagos/imunologia , Proteína da Síndrome de Wiskott-Aldrich/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Colite/prevenção & controle , Deleção de Genes , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Imunidade nas Mucosas , Interleucina-10/metabolismo , Interleucina-1beta/fisiologia , Interleucina-23/fisiologia , Mucosa Intestinal/imunologia , Macrófagos/citologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Síndrome de Wiskott-Aldrich/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética , Proteína da Síndrome de Wiskott-Aldrich/metabolismo
13.
Brain Behav Immun ; 70: 268-279, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29518529

RESUMO

TLX is an orphan nuclear receptor highly expressed within neural progenitor cells (NPCs) in the hippocampus where is regulates proliferation. Inflammation has been shown to have negative effects on hippocampal function as well as on NPC proliferation. Specifically, the pro-inflammatory cytokine IL-1ß suppresses NPC proliferation as well as TLX expression in the hippocampus. However, it is unknown whether TLX itself is involved in regulating the inflammatory response in the hippocampus. To explore the role of TLX in inflammation, we assessed changes in the transcriptional landscape of the hippocampus of TLX knockout mice (TLX-/-) compared to wildtype (WT) littermate controls with and without intrahippocampal injection of IL-1ß using a whole transcriptome RNA sequencing approach. We demonstrated that there is an increase in the transcription of genes involved in the promotion of inflammation and regulation of cell chemotaxis (Tnf, Il1b, Cxcr1, Cxcr2, Tlr4) and a decrease in the expression of genes relating to synaptic signalling (Lypd1, Syt4, Cplx2) in cannulated TLX-/- mice compared to WT controls. We demonstrate that mice lacking in TLX share a similar increase in 176 genes involved in regulating inflammation (e.g. Cxcl1, Tnf, Il1b) as WT mice injected with IL-1ß into the hippocampus. Moreover, TLX-/- mice injected with IL-1ß displayed a blunted transcriptional profile compared to WT mice injected with IL-1ß. Thus, TLX-/- mice, which already have an exaggerated inflammatory profile after cannulation surgery, are primed to respond differently to an inflammatory stimulus such as IL-1ß. Together, these results demonstrate that TLX regulates hippocampal inflammatory transcriptome response to brain injury (in this case cannulation surgery) and cytokine stimulation.


Assuntos
Receptores Nucleares Órfãos/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Animais , Proliferação de Células , Citocinas , Hipocampo/metabolismo , Inflamação , Interleucina-1beta/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células-Tronco Neurais/imunologia , Células-Tronco Neurais/fisiologia , Neurogênese , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais , Transcriptoma , Fator de Necrose Tumoral alfa
14.
Mol Immunol ; 97: 82-93, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29602073

RESUMO

BACKGROUND: The combinatorial effects of Plasmodium infection, perturbation of inflammatory responses and the dichotomic role of TNF promoter polymorphism has potential clinical and physiological relevance during pregnancy. OBJECTIVE AND METHODS: This coordinated orchestration instigated us to investigate the circulating level of inflammatory cytokines (IL-1ß, TNF-α and IL-6) employing ELISA in a stratified group of samples and the plausible genetic association of TNF-α -308 G/A using PCR-RFLP/sequencing during Plasmodium vivax infection in pregnancy. RESULTS: We observed significantly elevated concentrations of IL-1ß were observed, followed by IL-6 and TNF-α in women with malaria (WWM) and in malaria in pregnancy (MIP). Further, elevated IL-1ß, followed by TNF-α and IL-6 were detected in the non-infected pregnancy group. The differential dynamics of inflammatory cytokine concentration during each trimester of pregnancy with and without P. vivax infection were detected. For the first time, a high level of IL-6 was observed in the first trimester of MIP and high IL-1ß in healthy pregnancies. In the second trimester, however, we observed a high level of IL-1ß in the MIP group compared to a sustained high level of IL-1ß in the healthy pregnancy group. In the third trimester, high IL-1ß was sustained in the MIP group and healthy pregnancies acquired a high TNF-α level. The genotypic distribution for the TNF-α promoter -308 G/A position was observed to be nonsignificant and mildly associated during MIP (OR = 1.4) and in WWM (OR = 1.2). Moreover, based on genotypic distribution, we observed a well-correlated and significantly elevated TNF-α concentration in the mutant homozygote genotype (AA; p = 0.001) followed by heterozygotes (GA; p = 0.0001) and ancestral genotypes (GG; p = 0.0001) in both MIP and WWM subjects. CONCLUSION: The observation of elevated IL-1ß and IL-6 in MIP and TNF-α in WWM may be regarded as a prognostic inflammatory marker of infection and pregnancy. Most particularly, the TNF-α concentration and its polymorphic variability in the promoter region may indicate genetic susceptibility and mildly influence the risk for P. vivax infection during pregnancy and in women with malaria.


Assuntos
Interleucina-1beta/sangue , Interleucina-6/sangue , Malária Vivax/sangue , Malária Vivax/genética , Plasmodium vivax , Complicações Parasitárias na Gravidez , Fator de Necrose Tumoral alfa/genética , Adulto , Biomarcadores/sangue , Estudos Transversais , Doenças Endêmicas , Feminino , Predisposição Genética para Doença , Humanos , Índia/epidemiologia , Interleucina-1beta/fisiologia , Interleucina-6/fisiologia , Malária Vivax/epidemiologia , Malária Vivax/imunologia , Pessoa de Meia-Idade , Plasmodium vivax/imunologia , Polimorfismo Genético , Gravidez , Complicações Parasitárias na Gravidez/sangue , Complicações Parasitárias na Gravidez/epidemiologia , Complicações Parasitárias na Gravidez/genética , Complicações Parasitárias na Gravidez/imunologia , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/fisiologia , Adulto Jovem
15.
Cell Mol Biol Lett ; 23: 7, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29483929

RESUMO

Background: Osteoarthritis is characterized by the continuous degradation of the articular cartilage. The microRNA miR-448 has been found to be broadly involved in cellular processes, including proliferation, apoptosis, invasion and EMT. While aberrant expression of miR-448 has been found in multiple cancers, its level in osteoarthritis cartilage and its role in the progression of this disease are still unknown. Here, we examined the functional roles of miR-448 and its expression in osteoarthritis tissues, including IL-1ß-stimulated osteoarthritis chondrocytes. Methods: Chondrocytes were isolated from human articular cartilage and stimulated with IL-1ß. The expression levels of miR-448 in the cartilage and chondrocytes were both determined. After transfection with an miR-448 mimic or inhibitor, the mRNA levels of aggrecan, type II collagen and MMP-13 were determined. Luciferase reporter assay, qRT-PCR and western blot were performed to explore whether matrilin-3 was a target of miR-448. Furthermore, we co-transfected chondrocytes with miR-448 inhibitor and siRNA for matrilin-3 and then stimulated them with IL-1ß to determine whether miR-448-mediated IL-1ß-induced cartilage matrix degradation resulted from directly targeting matrilin-3. Results: The level of miR-448 was significantly higher and matrilin-3 expression was significantly lower in osteoarthritis cartilage and IL-1ß-induced chondrocytes than in normal tissues and cells. Furthermore, matrilin-3 expression was reduced by miR-448 overexpression. MiR-448 downregulation significantly alleviated the IL-1ß-induced downregulation of aggrecan and type II collagen expression, and upregulation of MMP-13 expression. MiR-448 overexpression had the opposite effects. Knockdown of matrilin-3 reversed the effects of the miR-448 inhibitor on the expressions of aggrecan, type II collagen and MMP-13. Conclusion: The findings showed that miR-448 contributed to the progression of osteoarthritis by directly targeting matrilin-3. This indicates that it has potential as a therapeutic target for the treatment of osteoarthritis.


Assuntos
Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Proteínas Matrilinas/genética , MicroRNAs/metabolismo , Osteoartrite/genética , Agrecanas/genética , Agrecanas/metabolismo , Células Cultivadas , Condrócitos/enzimologia , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/fisiologia , Proteínas Matrilinas/metabolismo , Metaloproteinase 13 da Matriz/biossíntese , MicroRNAs/fisiologia , Osteoartrite/metabolismo , RNA Mensageiro/metabolismo , Regulação para Cima
16.
J Agric Food Chem ; 66(4): 765-772, 2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29293001

RESUMO

Gouty arthritis is characterized by the precipitation of monosodium urate (MSU) crystals in the joint. Pro-inflammatory cytokine IL-1ß is a critical manifestation in response to MSU crystals attack. IL-1ß secretion is dependent on the nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Abnormal activation of the NLRP inflammasome is related to cellular oxidative stress. However, recent studies have illustrated that phytochemicals with potent antioxidant activity exert inhibitory effects on NLRP3 inflammasome-mediated diseases. This review focuses on the current findings of studies on the NLRP3 inflammasome and the proposed mechanisms that MSU crystals trigger inflammation via activation of the NLRP3 inflammasome. We also summarized the potential use of phytochemicals on NLRP3 inflammasome-mediated diseases, suggesting that phytochemicals can further prevent acute gout attack.


Assuntos
Gota/tratamento farmacológico , Inflamassomos/química , Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/análise , Compostos Fitoquímicos/uso terapêutico , Animais , Antioxidantes , Cristalização , Dieta , Flavonoides/administração & dosagem , Flavonoides/uso terapêutico , Gota/etiologia , Humanos , Inflamassomos/efeitos dos fármacos , Interleucina-1beta/fisiologia , Compostos Fitoquímicos/administração & dosagem , Fitoterapia , Resveratrol , Estilbenos/administração & dosagem , Estilbenos/uso terapêutico , Ácido Úrico/efeitos adversos , Ácido Úrico/sangue , Ácido Úrico/química
17.
Neuron ; 97(2): 299-312.e6, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29290552

RESUMO

Microglia exhibit two modes of motility: they constantly extend and retract their processes to survey the brain, but they also send out targeted processes to envelop sites of tissue damage. We now show that these motility modes differ mechanistically. We identify the two-pore domain channel THIK-1 as the main K+ channel expressed in microglia in situ. THIK-1 is tonically active, and its activity is potentiated by P2Y12 receptors. Inhibiting THIK-1 function pharmacologically or by gene knockout depolarizes microglia, which decreases microglial ramification and thus reduces surveillance, whereas blocking P2Y12 receptors does not affect membrane potential, ramification, or surveillance. In contrast, process outgrowth to damaged tissue requires P2Y12 receptor activation but is unaffected by blocking THIK-1. Block of THIK-1 function also inhibits release of the pro-inflammatory cytokine interleukin-1ß from activated microglia, consistent with K+ loss being needed for inflammasome assembly. Thus, microglial immune surveillance and cytokine release require THIK-1 channel activity.


Assuntos
Interleucina-1beta/fisiologia , Microglia/fisiologia , Canais de Potássio de Domínios Poros em Tandem/fisiologia , Trifosfato de Adenosina/farmacologia , Animais , Movimento Celular , Polaridade Celular , Forma Celular , Extensões da Superfície Celular/fisiologia , Quimiotaxia/fisiologia , Inflamassomos/metabolismo , Potenciais da Membrana , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Potássio/fisiologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/deficiência , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y12/fisiologia , Transcriptoma
18.
Bull Math Biol ; 80(3): 540-582, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29349609

RESUMO

Caspase-1-mediated pyroptosis is the predominance for driving CD4[Formula: see text] T cells death. Dying infected CD4[Formula: see text] T cells can release inflammatory signals which attract more uninfected CD4[Formula: see text] T cells to die. This paper is devoted to developing a diffusive mathematical model which can make useful contributions to understanding caspase-1-mediated pyroptosis by inflammatory cytokines IL-1[Formula: see text] released from infected cells in the within-host environment. The well-posedness of solutions, basic reproduction number, threshold dynamics are investigated for spatially heterogeneous infection. Travelling wave solutions for spatially homogeneous infection are studied. Numerical computations reveal that the spatially heterogeneous infection can make [Formula: see text], that is, it can induce the persistence of virus compared to the spatially homogeneous infection. We also find that the random movements of virus have no effect on basic reproduction number for the spatially homogeneous model, while it may result in less infection risk for the spatially heterogeneous model, under some suitable parameters. Further, the death of infected CD4[Formula: see text] cells which are caused by pyroptosis can make [Formula: see text], that is, it can induce the extinction of virus, regardless of whether or not the parameters are spatially dependent.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Caspase 1/fisiologia , Piroptose/fisiologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Simulação por Computador , Infecções por HIV/patologia , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , Humanos , Interleucina-1beta/fisiologia , Conceitos Matemáticos , Modelos Biológicos
19.
Proc Natl Acad Sci U S A ; 115(6): E1194-E1203, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29358392

RESUMO

Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1ß-knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1ß/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1ß expression by inflammatory CCR2hi monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1ß, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4+ T cells. Factors released from the interaction between IL-1ß-competent myeloid cells and CD4+ T cells are highly toxic to neurons. Together, our results suggest that IL-1ß signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.


Assuntos
Linfócitos T CD4-Positivos/patologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/patologia , Interleucina-1beta/fisiologia , Monócitos/patologia , Neurônios/patologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/metabolismo , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Neurônios/imunologia , Neurônios/metabolismo , Receptores CCR2/metabolismo
20.
Inflamm Res ; 67(4): 327-337, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29256007

RESUMO

OBJECTIVE AND DESIGN: Epigenetic regulation is important in the activation of inflammatory cells. In the present study, we evaluated if DNA-methylation variations are involved in Interleukin-1ß (IL-1ß)-induced intestinal epithelial cells activation. MATERIALS AND METHODS: Differentiated Caco-2 cells were exposed to IL-1ß or to 5-azadeoxycytidine (5-azadC) for 24 or 48 h. Genome-wide methylation status was evaluated, while DNA methylation status at the promoter region of the gene encoding interleukin-6, 8 and 10 (IL-6, 8 and 10) was estimated. The levels of the corresponding gene products as well as DNA methyltransferases (DNMTs) quantity were assessed. RESULTS: IL-1ß decreased genomic methylation of human intestinal epithelial cells and induced demethylation at cg-specific sites at the promoter of pro-inflammatory genes IL6 and IL8; conversely it did not change the methylation of the IL10 promoter. IL-1ß also increased the release of IL-6 and IL-8 but did not change the IL-10 expression. Finally, cell exposure to IL-1ß decreased the DNMT3b expression, increased DNMT3a and was not able to change DNMT1 expression. CONCLUSIONS: Our results suggest a potential role of IL-1ß as modulator of DNA methylation in activated differentiated Caco-2 cell line.


Assuntos
Metilação de DNA , Interleucina-1beta/fisiologia , Interleucinas/genética , Mucosa Intestinal/metabolismo , Regiões Promotoras Genéticas , Células CACO-2 , Metilases de Modificação do DNA/metabolismo , Epigênese Genética , Humanos , Mediadores da Inflamação/metabolismo , Interleucinas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA