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1.
Biochem Biophys Res Commun ; 604: 83-87, 2022 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-35303683

RESUMO

BACKGROUND: Vascular calcification is characterized by mineral deposition in the vasculature, which is triggered by chronic systemic inflammation, including psoriasis. Psoriasis is an IL-17A-mediated inflammatory skin disease that is associated with exacerbated vascular calcification and high cardiovascular mortality. Although previous studies have shown that IL-17A induces vascular dysfunction in murine psoriasis models, it has not been clarified whether IL-17A induces vascular calcification. In this study, we investigated the potential vascular calcification-inducing effect of IL-17A in an ex vivo culture system. METHODS: Thoracic and abdominal aortas from mice were cultured in a medium supplemented with inorganic phosphate and were treated with inflammatory cytokines (IL-1ß, TNF-α, IL-6, and IL-17A). Vascular calcification was determined using micro-computed tomography (CT) and histological analyses. RESULTS: IL-1ß, TNF-α, and IL-6 did not significantly promote vascular calcification, whereas IL-17A significantly accelerated vascular calcification of the aorta, as indicated by the increased mineralized volume based on micro-CT analysis. Micro-CT and histological analyses also revealed that the promoting effect of IL-17A on vascular calcification was concentration dependent. CONCLUSIONS: IL-17A significantly promoted vascular calcification in ex vivo cultured aortas, which suggests that this mechanism is involved in the increased risk of cardiovascular events in IL-17A-mediated inflammatory diseases.


Assuntos
Interleucina-17 , Psoríase , Calcificação Vascular , Animais , Aorta Abdominal , Inflamação/complicações , Interleucina-17/farmacologia , Interleucina-17/fisiologia , Interleucina-6/farmacologia , Camundongos , Psoríase/complicações , Fator de Necrose Tumoral alfa/farmacologia , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Microtomografia por Raio-X
2.
Dermatol Ther ; 32(4): e12849, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30707471

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease of uncertain etiology that affects multiple tissues and organs. Tetra-arsenic tetra-sulfide (As4 S4 ), a traditional Chinese medicine, is effective on acute promyelocytic leukemia with mild side effects. In our previous study, BXSB lupus-prone mice treated with As4 S4 has showed improved monocytosis, decreased serum interleukin (IL)-6 and suppressed skin, liver and renal lesions with well-tolerance. In this study, we explored the effect and mechanism of As4 S4 on the MRL/lpr mice. MRL/lpr and wild MRL/MpJ mice were divided into control and As4 S4 treatment groups and dosed with As4 S4 or placebo for 8 weeks. We found that As4 S4 prevented the skin, renal and lung lesions of MRL/lpr mice. As4 S4 significantly decreased the double negative T (DN T) cells and reduced the serum levels of IL-17, IL-10, and antinuclear antibodies titer. Further results revealed that the FasL was decreased, and activated caspases elevated in DN T cells in As4 S4 treated MRL/lpr mice. Taken together, As4 S4 could selectively suppresses DN T cells by inducing apoptosis. It also reduced inflammatory cytokines IL-17, which may be produced by DN T cells. As4 S4 may represent a new therapy for SLE.


Assuntos
Arsenicais/uso terapêutico , Interleucina-17/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Sulfetos/uso terapêutico , Linfócitos T/efeitos dos fármacos , Animais , Arsenicais/farmacologia , Feminino , Interleucina-10/fisiologia , Interleucina-17/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Camundongos , Camundongos Endogâmicos MRL lpr , Tamanho do Órgão/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia , Sulfetos/farmacologia , Linfócitos T/imunologia
3.
Am J Pathol ; 187(5): 1049-1058, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28284716

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints. High-fat diet (HFD) is a risk factor for RA and is related to inflammation but responds minimally to medication. Given the association between HFD and inflammation, it is important to understand the function of inflammation-related T cells in RA with HFD. Collagen-induced arthritis (CIA), a model of RA, was induced in HFD mice by injection of collagen II, and metabolic markers and T cells were analyzed. The metabolic index and IgG assay results were higher in HFD-CIA mice than in nonfat diet-CIA mice. Numbers of inflammation-related T cells and macrophages, such as Th1 and Th17 cells and M1 macrophages, were higher in spleens of HFD-CIA mice. HFD-CIA mice had a high level of α2-glycoprotein 1 (Azgp1), a soluble protein that stimulates lipolysis. To examine the association between Azgp1 and Th17 cells, the reciprocal effects of Azgp1 and IL-17 on Th17 differentiation and lipid metabolism were measured. Interestingly, Azgp1 increased the Th17 population of splenocytes. Taken together, our data suggest that the acceleration of fat loss caused by Azgp1 in RA with metabolic syndrome is related to the increase of IL-17. Mice injected with the Azgp1-overexpression vector exhibited more severe CIA compared with the mock vector-injected mice.


Assuntos
Artrite Reumatoide/etiologia , Dieta Hiperlipídica/efeitos adversos , Interleucina-17/fisiologia , Células Th17/fisiologia , Animais , Artrite Experimental/induzido quimicamente , Diferenciação Celular/fisiologia , Colágeno Tipo II/toxicidade , Vetores Genéticos/administração & dosagem , Vetores Genéticos/farmacologia , Glicogênio/metabolismo , Imunoglobulinas/metabolismo , Interleucina-17/farmacologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Doenças Metabólicas/fisiopatologia , Camundongos Endogâmicos DBA , Proteínas Recombinantes/farmacologia , Proteínas de Plasma Seminal/metabolismo , Baço/citologia , Linfócitos T Reguladores/fisiologia , Regulação para Cima/fisiologia , Glicoproteína Zn-alfa-2
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(2): 190-5, 2015 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-25760848

RESUMO

OBJECTIVE: To study the effects of 1,25-(OH)(2)D(3) on airway remodeling and expression of high mobility group box 1 (HMGB1) and IL-17 in asthmatic mice. METHODS: Fifty female mice were randomly divided into 5 groups: control, asthma, low-dose, middle-dose, and high-dose intervention groups (n=10 each). Asthma was induced by intraperitoneal injections of ovalbumin (OVA) and aerosol inhalation of OVA solution. The low-dose, middle-dose, and high-dose intervention groups were administered with 1,25-(OH)(2)D(3) solution at the dosage of 1, 4 and 10 µg/kg respectively by intraperitoneal injections before asthma challenge. The airway structural changes were assessed by hematoxylin and eosin staining. mRNA expression levels of HMGB1 and IL-17 in the lung tissues were evaluated by RT-PCR. The protein levels of HMGB1 and IL-17 in the lung tissues were observed by immunohistochemistry. RESULTS: The airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 were higher in the untreated asthma group than in the control group (P<0.05). The airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 were lower in the middle-dose and low-dose intervention groups than in the untreated asthma group, and the middle-dose intervention group demonstrated lower airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 than in the low-dose intervention group (P<0.05). However, the airway wall thickness, protein and mRNA expression levels of HMGB1 and IL-17 in the high-dose intervention group were higher than in the untreated asthma group (P<0.05). CONCLUSIONS: HMGB1 and IL-17 may be involved in the airway remodeling process in asthmatic mice. A moderate amount of HMGB1 and IL-17 may be involved in the airway remodeling process in asthmatic mice. A moderate amount of 1,25-(OH)(2)D(3) can improve the airway remodeling, but a higher dose of 1,25-(OH)(2)D(3) may affect adversely the airway remodeling process.


Assuntos
Asma/tratamento farmacológico , Calcitriol/farmacologia , Proteína HMGB1/fisiologia , Interleucina-17/fisiologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/metabolismo , Asma/patologia , Relação Dose-Resposta a Droga , Feminino , Proteína HMGB1/análise , Proteína HMGB1/genética , Interleucina-17/análise , Interleucina-17/genética , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C
6.
Expert Opin Biol Ther ; 14(4): 515-26, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24555741

RESUMO

INTRODUCTION: Psoriatic arthritis (PsA) is a clinically diverse inflammatory arthritis that can affect peripheral joints and the axial skeleton. About 25% of psoriasis patients develop PsA and many suffer from reduced function and quality of life. Anti-TNF agents have emerged as a pivotal treatment for many patients but the lack of alternative biologics for those who become unresponsive and or tolerate these medications remain a major unmet need. Recently, ustekinumab (UST) an agent that targets the 12 - 23/Th17 pathway was approved by the FDA for the treatment of active PsA. AREAS COVERED: Herein, we provide a comprehensive overview of the pharmacology and clinical efficacy and safety of UST in the treatment of PsA. In addition, the position of UST in the treatment of PsA is discussed. EXPERT OPINION: The lack of alternative therapies for patients who cannot tolerate or fail anti-TNF agents remains a major challenge for clinicians who treat PsA. UST, an agent that has proven efficacy in psoriasis, has recently been shown to also be effective for a number of the manifestations associated with PsA, including peripheral arthritis, dactylitis and enthesitis. This agent also inhibits radiographic progression. FDA approval of UST provides a much needed addition to the treatment options for the heterogeneous clinical features of PsA.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Interleucina-17/fisiologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/farmacocinética , Antirreumáticos/uso terapêutico , Aprovação de Drogas , Humanos , Metotrexato/uso terapêutico , Psoríase/tratamento farmacológico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Ustekinumab
7.
Mol Immunol ; 47(15): 2467-74, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20615550

RESUMO

Triptolide is an active component of extracts derived from the medicinal vine Tripterygium Wilfordii Hook. f. (TWHF) whose extracts have been used to treat inflammatory bowel disease (IBD). We have reported that triptolide showed therapeutic activity in a murine IBD model, but the potential mechanism of action of this agent in IBD remains elusive. Accumulated data showed that both T-helper (Th) 1 and Th17 response may contribute to pathogenesis of human IBD and animal colitis. Interleukin (IL)-6/signal transducer and activator of transcription-3 (STAT3) signaling pathway play an important role in Th17 response as well as pathophysiology of IBD. We hypothesized that triptolide would attenuate the experimental colitis by repressing IL-17 and that this would involve down-regulation of IL-6/STAT3 signaling pathway. Histological examination demonstrated that triptolide significantly reduced the severity of colitis in C3H/HeJBir.IL-10-deficeint mice. Triptolide suppressed the IL-6/STAT3 signaling pathway, as well as repressed gene expression of IL-17 in vivo. In addition, triptolide (20ng/ml) in vitro was able to down-regulate the IL-6/STAT3 pathway and reduce IL-17 expression in cultured colonic explants from patients with Crohn's disease (CD).


Assuntos
Colite/tratamento farmacológico , Doença de Crohn/patologia , Diterpenos/farmacologia , Imunossupressores/farmacologia , Interleucina-10/deficiência , Interleucina-17/fisiologia , Interleucina-6/antagonistas & inibidores , Fenantrenos/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Colo/efeitos dos fármacos , Receptor gp130 de Citocina/fisiologia , Diterpenos/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Interleucina-10/fisiologia , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucina-6/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , Técnicas de Cultura de Órgãos , Fenantrenos/uso terapêutico , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos
8.
J Immunol ; 183(1): 191-200, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19542430

RESUMO

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease characterized by chronic joint inflammation with subsequent cartilage and bone destruction. RA is emerging as a model of IL-17-driven autoimmune inflammatory disease. IL-17 is a marker for Th17 cells, with its master regulator being the retinoic acid receptor-related orphan receptor (RORgammat) regulated by STAT3 signaling. Glucuronoxylomannan (GXM), a polysaccharide representing the main component of the capsular material of the opportunistic yeast Cryptococcus neoformans, exhibits potent immunosuppressive properties both in vitro and in vivo. The present study investigates the effects of GXM treatment on the progression of collagen-induced arthritis. GXM suppressed clinical signs of collagen-induced arthritis and blocked joint erosion progression. This effect was mediated by down-regulation of key cytokines involved in the pathogenesis of RA such as TNF-alpha and IL-1beta, and up-regulation of the inhibitory cytokine IL-10. Moreover, a reduction of IL-6 and TGF-beta, which inhibit Th17 differentiation with consequent decreased IL-17 production at the local and systemic level, was observed. The effect of GXM on Th17 differentiation mirrored the reduction in STAT3 activation and inhibition of RORgammat synthesis. Consequently, this work highlights the beneficial properties of an efficacious compound that could eventually be destined to the clinic.


Assuntos
Artrite Reumatoide/imunologia , Cryptococcus neoformans/imunologia , Citocinas/biossíntese , Imunossupressores/administração & dosagem , Mediadores da Inflamação/metabolismo , Interleucina-17/fisiologia , Polissacarídeos/administração & dosagem , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos de Fungos/administração & dosagem , Antígenos de Fungos/imunologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/epidemiologia , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Reabsorção Óssea/imunologia , Reabsorção Óssea/patologia , Colágeno Tipo II/toxicidade , Citocinas/antagonistas & inibidores , Citocinas/fisiologia , Imunossupressores/imunologia , Incidência , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/fisiologia , Interleucina-17/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos DBA , Osteoclastos/imunologia , Osteoclastos/patologia , Polissacarídeos/imunologia , Polissacarídeos/uso terapêutico , Ligante RANK/biossíntese , Ligante RANK/genética , Índice de Gravidade de Doença , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia
9.
J Immunol ; 182(6): 3928-36, 2009 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19265172

RESUMO

IFN-beta, an effective therapy against relapsing-remitting multiple sclerosis, is naturally secreted during the innate immune response against viral pathogens. The objective of this study was to characterize the immunomodulatory mechanisms of IFN-beta targeting innate immune response and their effects on dendritic cell (DC)-mediated regulation of T cell differentiation. We found that IFN-beta1a in vitro treatment of human monocyte-derived DCs induced the expression of TLR7 and the members of its downstream signaling pathway, including MyD88, IL-1R-associated kinase 4, and TNF receptor-associated factor 6, while it inhibited the expression of IL-1R. Using small interfering RNA TLR7 gene silencing, we confirmed that IFN-beta1a-induced changes in MyD88, IL-1R-associated kinase 4, and IL-1R expression were dependent on TLR7. TLR7 expression was also necessary for the IFN-beta1a-induced inhibition of IL-1beta and IL-23 and the induction of IL-27 secretion by DCs. Supernatant transfer experiments confirmed that IFN-beta1a-induced changes in DC cytokine secretion inhibit Th17 cell differentiation as evidenced by the inhibition of retinoic acid-related orphan nuclear hormone receptor C and IL-17A gene expression and IL-17A secretion. Our study has identified a novel therapeutic mechanism of IFN-beta1a that selectively targets the autoimmune response in multiple sclerosis.


Assuntos
Citocinas/antagonistas & inibidores , Células Dendríticas/metabolismo , Interferon beta/fisiologia , Interleucina-17/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Receptor 7 Toll-Like/fisiologia , Regulação para Cima/imunologia , Adjuvantes Imunológicos/fisiologia , Autoanticorpos/biossíntese , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Polaridade Celular/imunologia , Células Cultivadas , Quimiocinas/biossíntese , Quimiocinas/genética , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Inibidores do Crescimento/genética , Inibidores do Crescimento/metabolismo , Inibidores do Crescimento/fisiologia , Humanos , Mediadores da Inflamação/metabolismo , Interferon beta-1a , Interleucina-17/fisiologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Receptor 7 Toll-Like/biossíntese , Receptor 7 Toll-Like/genética , Regulação para Cima/genética
10.
Cytokine Growth Factor Rev ; 14(2): 155-74, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12651226

RESUMO

Interleukin-17 (IL-17) is a pro-inflammatory cytokine secreted by activated T-cells. Recently discovered related molecules are forming a family of cytokines, the IL-17 family. The prototype member of the family has been designated IL-17A. Due to recent advances in the human genome sequencing and proteomics five additional members have been identified and cloned: IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The cognate receptors for the IL-17 family identified thus far are: IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and IL-17RE. However, the ligand specificities of many of these receptors have not been established. The IL-17 signaling system is operative in disparate tissues such as articular cartilage, bone, meniscus, brain, hematopoietic tissue, kidney, lung, skin and intestine. Thus, the evolving IL-17 family of ligands and receptors may play an important role in the homeostasis of tissues in health and disease beyond the immune system. This survey reviews the biological actions of IL-17 signaling in cancers, musculoskeletal tissues, the immune system and other tissues.


Assuntos
Interleucina-17/fisiologia , Receptores de Interleucina/fisiologia , Sequência de Aminoácidos , Artrite/metabolismo , Cartilagem/metabolismo , Cartilagem Articular/metabolismo , Modelos Animais de Doenças , Ligantes , Microscopia de Fluorescência , Modelos Biológicos , Modelos Genéticos , Dados de Sequência Molecular , Neoplasias/metabolismo , Filogenia , Proteínas Recombinantes , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Linfócitos T/metabolismo , Distribuição Tecidual
11.
J Immunol ; 165(3): 1395-402, 2000 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-10903743

RESUMO

IFN-induced protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC) belong to the non-glutamate-leucine-arginine motif CXC chemokine family and act solely through the CXCR3 receptor for potent attraction of T lymphocytes. In this study, we evaluated the capacity of the T cell-derived cytokines IL-4, IL-10, and IL-17 to modulate IP-10, Mig, and I-TAC in cultured human keratinocytes and CXCR3 expression in T cells from allergic contact dermatitis (ACD). IL-4, but not IL-10 or IL-17, significantly up-regulated IFN-gamma- or TNF-alpha-induced IP-10, Mig, and I-TAC mRNA accumulation in keratinocytes and increased the levels of IP-10 and Mig in keratinocyte supernatants. Immunohistochemistry of skin affected by ACD revealed that >70% of infiltrating cells were reactive for CXCR3 and that CXCR3 staining colocalized in CD4+ and CD8+ T cells. Nickel-specific CD4+ and CD8+ T cell lines established from ACD skin produced IFN-gamma and IL-4 and expressed moderate to high levels of CXCR3. Finally, CXCR3 agonistic chemokines released by stimulated keratinocytes triggered calcium mobilization in skin-derived nickel-specific CD4+ T cells and promoted their migration, with supernatant from keratinocyte cultures stimulated with IFN-gamma and IL-4 attracting more efficaciously than supernatant from keratinocytes activated with IFN-gamma alone. In conclusion, IL-4 exerts a proinflammatory function on keratinocytes by potentiating IFN-gamma and TNF-alpha induction of IP-10, Mig, and I-TAC, which in turn may determine a prominent recruitment of CXCR3+ T lymphocytes at inflammatory reaction sites.


Assuntos
Adjuvantes Imunológicos/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-4/fisiologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Receptores de Quimiocinas/agonistas , Receptores de Quimiocinas/biossíntese , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Cálcio/metabolismo , Sinalização do Cálcio/imunologia , Linhagem Celular , Movimento Celular/imunologia , Sistema Livre de Células/imunologia , Quimiocina CXCL10 , Quimiocina CXCL11 , Quimiocina CXCL9 , Quimiocinas CXC/biossíntese , Dermatite Alérgica de Contato/imunologia , Dermatite Alérgica de Contato/metabolismo , Dermatite Alérgica de Contato/patologia , Humanos , Interferon gama/farmacologia , Interleucina-10/fisiologia , Interleucina-17/fisiologia , Níquel/imunologia , Receptores CXCR3 , Pele/imunologia , Pele/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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