Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Transl Med ; 18(1): 483, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33317573

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. METHODS: We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysis. RESULTS: We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3 + Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset. CONCLUSIONS: Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.


Assuntos
Doença Enxerto-Hospedeiro , Células Supressoras Mieloides , Doença Aguda , Animais , Doença Enxerto-Hospedeiro/terapia , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Células Th17
2.
J Transl Med ; 18(1): 186, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370746

RESUMO

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease mediated by lymphocytic infiltration into exocrine glands, resulting in progressive lacrimal and salivary destruction and dysfunctional glandular secretion. Metabolic syndrome influences the immune system. To investigate its relationship with metabolic abnormalities, we evaluated the pathogenesis of SS and the immune cell populations in non-obese diabetic NOD/ShiLtJ mice with type 1 diabetes (T1D). METHODS: To induce metabolic abnormalities, streptozotocin (STZ)-a glucosamine-nitrosourea compound that destroys pancreatic ß cells, resulting in T1D-was injected into NOD/ShiLtJ mice. The blood glucose level was measured to evaluate induction of T1D. The severity of SS was assessed by determining the body weight, salivary flow rate, and histologic parameters. The expression levels of proinflammatory factors in the salivary glands, lacrimal gland, and spleen were quantified by real-time PCR. The populations of various T- and B-cell subtypes in the peripheral blood, spleen, and salivary glands were assessed by flow cytometry. RESULTS: Induction of T1D in NOD/ShiLtJ mice increased both the severity of SS and the levels of proinflammatory cytokines in the salivary glands compared to the controls. Furthermore, the number of interleukin-17-producing immune cells in the peripheral blood, spleen, and salivary glands was increased in STZ- compared to vehicle-treated NOD/ShiLtJ mice. CONCLUSIONS: Metabolic abnormalities play an important role in the development of SS.


Assuntos
Síndrome de Sjogren , Animais , Modelos Animais de Doenças , Interleucina-17 , Camundongos , Camundongos Endogâmicos NOD , Glândulas Salivares
3.
FASEB J ; 34(1): 248-262, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914604

RESUMO

This study was aimed at investigating the therapeutic effects of BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, on the development of autoimmune arthritis in humans and mice. To verify the effects of BITRAP in human, peripheral blood mononuclear cells were cultured with BITRAP under IL-17-producing T (Th17) cell-polarizing conditions or osteoclast differentiation conditions. BITRAP treatment inhibited the production of IL-17 and vascular endothelial growth factor but increased the production of IL-10 in CD4+ T cells, as well as directly suppressed osteoclastogenesis. Collagen-induced arthritis (CIA) and IL-1R antagonist (IL-1Ra) knockout mice were treated with BITRAP. Following injection in CIA mice, BITRAP rapidly migrated into the inflamed joints and remained there for 72 hours. Application of BITRAP attenuated the severity of autoimmune arthritis in CIA and IL-1Ra knockout mice by reducing the numbers of inflammatory cytokine-expressing cells and Th17 cells and antibody secretion. Finally, BITRAP suppressed STAT3 phosphorylation, as well as production of IL-17 and TNF-α, in murine splenic CD4+ T cells. These findings suggest that BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, may be an effective treatment to overcome the limitations of anti-TNF therapy for patients with rheumatoid arthritis.


Assuntos
Artrite/tratamento farmacológico , Interleucinas/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Fatores de Coagulação Sanguínea , Linfócitos T CD4-Positivos , Fibroblastos , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Imunoglobulinas/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Osteogênese/efeitos dos fármacos , Engenharia de Proteínas , Proteínas Recombinantes , Células Th17 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Cytokine ; 125: 154834, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491724

RESUMO

Sjögren's syndrome (SS) is a systemic autoimmune disease with severe dysfunction of glandular secretory function mediated by T and B lymphocyte infiltration into the exocrine glands, including the salivary and lacrimal glands. Follicular helper T (Tfh) cells exacerbate the disease by causing B cell hyperactivity. Inhibitor of DNA binding 3 (Id3) deficiency causes activation of Tfh cells and is known to be a clinical manifestation of human SS disease. In this study, we investigated the mechanism of action of Pax3, which is reduced in SS and can interact with Id3, in NOD/ShiLtJ mice as an animal model of SS. Treatment with interleukin (IL)-21, a major cytokine secreted from Tfh cells, suppressed Pax3 and Id3 expression via STAT3 in splenic T cells in vitro. Administration of pCMV14-3xFlag PAX3 vector improved the severity of SS by reducing the number of Tfh cells in NOD/ShiLtJ mice. Application of IL-21R-Fc increased the number of Pax3- and Id3-positive cells in the salivary glands, while reducing the proportion of Tfh cells and IL-17-producing T cells in NOD/ShiLtJ mice. The salivary glands from SS patients showed decreased levels of Pax3 or Id3 expression compared with healthy controls. Our findings regarding reinforcement of the Pax3-Id3 signal pathway may facilitate the development of novel therapeutic strategies for SS.


Assuntos
Proteínas Inibidoras de Diferenciação/metabolismo , Interleucinas/farmacologia , Proteínas de Neoplasias/metabolismo , Fator de Transcrição PAX3/metabolismo , Síndrome de Sjogren/imunologia , Células T Auxiliares Foliculares/imunologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Diferenciação/antagonistas & inibidores , Interleucina-17/metabolismo , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Proteínas de Neoplasias/antagonistas & inibidores , Fator de Transcrição PAX3/genética , Fator de Transcrição STAT3/metabolismo , Glândulas Salivares/efeitos dos fármacos , Glândulas Salivares/metabolismo , Transdução de Sinais/efeitos dos fármacos , Síndrome de Sjogren/genética , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/terapia , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Regulação para Cima
5.
Mediators Inflamm ; 2019: 5648987, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31780863

RESUMO

Rheumatoid arthritis (RA) is a type of systemic autoimmune arthritis that causes joint inflammation and destruction. One of the pathological mechanisms of RA is known to involve histone acetylation. Although the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) can attenuate arthritis in animal models of RA, the mechanism underlying this effect is poorly understood. This study was performed to examine whether SAHA has therapeutic potential in an animal model of RA and to investigate its mechanism of action. Collagen-induced arthritis (CIA) mice were orally administered SAHA daily for 8 weeks and examined for their arthritis score and incidence of arthritis. CD4+ T cell regulation following SAHA treatment was confirmed in splenocytes cultured under type 17 helper T (Th17) cell differentiation conditions. Clinical scores and the incidence of CIA were lower in mice in the SAHA treatment group compared to the controls. In addition, SAHA inhibited Th17 cell differentiation, as well as decreased expression of the Th17 cell-related transcription factors pSTAT3 Y705 and pSTAT3 S727. In vitro experiments showed that SAHA maintained regulatory T (Treg) cells but specifically reduced Th17 cells. The same results were obtained when mouse splenocytes were cultured under Treg cell differentiation conditions and then converted to Th17 cell differentiation conditions. In conclusion, SAHA was confirmed to specifically inhibit Th17 cell differentiation through nuclear receptor subfamily 1 group D member 1 (NR1D1), a factor associated with Th17 differentiation. The results of the present study suggested that SAHA can attenuate CIA development by inhibition of the Th17 population and maintenance of the Treg population through NR1D1 inhibition. Therefore, SAHA is a potential therapeutic candidate for RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/metabolismo , Células Th17/metabolismo , Vorinostat/uso terapêutico , Animais , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Masculino , Camundongos , Microscopia Confocal , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos
6.
Front Immunol ; 10: 1526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379809

RESUMO

Optimizing Treg function and improving Treg stability are attractive treatment strategies for treating autoimmune rheumatoid arthritis (RA). However, the limited number of circulating Tregs and questions about the functional stability of in vitro-expanded Tregs are potential limitations of Treg-based cell therapy. The aim of this study was to analyze the regulatory effect of daurinol, a catalytic inhibitor of topoisomerase IIα, on Th cell differentiation and to evaluate their therapeutic potential in a preclinical experimental model of RA. We investigated the effect of daurinol on T cell differentiation by flow cytometry. Foxp3 stability and methylation were analyzed by suppression assays and bisulfite pyrosequencing. Daurinol was treated in the collagen-induced arthritis (CIA) model, and the effects in vivo were determined. We found that daurinol can promote Treg differentiation and reciprocally inhibit Th17 differentiation. This Treg-inducing property of daurinol was associated with decreased activity of Akt-mTOR and reciprocally increased activity of neuropilin-1 (Nrp1)-PTEN. Daurinol treatment inhibited aerobic glycolysis in Th17 conditions, indicating the metabolic changes by daurinol. We found that the daurinol increase the Treg stability was achieved by Foxp3 hypomethylation. In vivo daurinol treatment in CIA mice reduced the clinical arthritis severity and histological inflammation. The Treg population frequency increased and the Th17 cells decreased in the spleens of arthritis mice treated with daurinol. These results showed the anti-arthritic and immunoregulating properties of daurinol is achieved by increased differentiation and stabilization of Tregs. Our study provides first evidence for daurinol as a treatment for RA.


Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Fatores de Transcrição Forkhead/imunologia , Neuropilina-1/imunologia , PTEN Fosfo-Hidrolase/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Artrite Experimental/imunologia , Diferenciação Celular/imunologia , Citocinas/imunologia , Humanos , Inflamação/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Células Th17/imunologia
7.
Arthritis Res Ther ; 21(1): 136, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31164166

RESUMO

BACKGROUND: Activated T and B cells participate in the development and progression of Sjögren's syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS. METHODS: Metformin or vehicle was administered orally to the mice for 9 weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20 weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4+ T and B cell differentiation in the peripheral blood and/or spleen was determined by flow cytometry. Serum total IgG, IgG1, and IgG2a levels were determined by enzyme-linked immunosorbent assay. RESULTS: Metformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-α, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells. CONCLUSION: Metformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS.


Assuntos
Imunidade Inata/efeitos dos fármacos , Metformina/administração & dosagem , Glândulas Salivares/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Administração Oral , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Hipoglicemiantes/administração & dosagem , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos NOD , Microscopia Confocal , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Sialadenite , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Linfócitos T Reguladores/patologia
8.
J Immunol ; 203(1): 127-136, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31142603

RESUMO

Mesenchymal stem cells (MSCs) can protect against cartilage breakdown in osteoarthritis (OA) via their immunomodulatory capacities. However, the optimization strategy for using MSCs remains challenging. This study's objective was to identify the in vivo effects of metformin-stimulated adipose tissue-derived human MSCs (Ad-hMSCs) in OA. An animal model of OA was established by intra-articular injection of monosodium iodoacetate into rats. OA rats were divided into a control group and two therapy groups (treated with Ad-hMSCs or metformin-stimulated Ad-hMSCs). Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Our data show that metformin increased IL-10 and IDO expression in Ad-hMSCs and decreased high-mobility group box 1 protein, IL-1ß, and IL-6 expression. Metformin increased the migration capacity of Ad-hMSCs with upregulation of chemokine expression. In cocultures, metformin-stimulated Ad-hMSCs inhibited the mRNA expression of RUNX2, COL X, VEGF, MMP1, MMP3, and MMP13 in IL-1ß-stimulated OA chondrocytes and increased the expression of TIMP1 and TIMP3. The antinociceptive activity and chondroprotective effects were greater in OA rats treated with metformin-stimulated Ad-hMSCs than in those treated with unstimulated Ad-hMSCs. TGF-ß expression in subchondral bone of OA joints was attenuated more in OA rats treated with metformin-stimulated Ad-hMSCs. Our findings suggest that metformin offers a promising option for the clinical application of Ad-hMSCs as a cell therapy for OA.


Assuntos
Tecido Adiposo/citologia , Anti-Inflamatórios/metabolismo , Condrócitos/fisiologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/fisiologia , Metformina/metabolismo , Osteoartrite/terapia , Animais , Movimento Celular , Células Cultivadas , Citoproteção , Difosfatos , Modelos Animais de Doenças , Humanos , Imidazóis , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-10/metabolismo , Masculino , Nociceptividade , Ratos , Ratos Wistar
10.
Immunology ; 156(4): 413-421, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30585643

RESUMO

CR6-interacting factor 1 (CRIF1) is a nuclear protein that interacts with other nuclear factors and androgen receptors, and is implicated in the regulation of cell cycle progression and cell growth. In this study, we examined whether CRIF1 exerts an immunoregulatory effect by modulating the differentiation and function of pathogenic T cells. To this end, the role of CRIF1 in rheumatoid arthritis, a systemic autoimmune disease characterized by hyperplasia of synovial tissue and progressive destruction of articular cartilage structure by pathogenic immune cells [such as T helper type 17 (Th17) cells], was investigated. p3XFLAG-CMV-10-CRIF1 was administered to mice with collagen-induced arthritis 8 days after collagen type II immunization and the disease severity and histologic evaluation, and osteoclastogenesis were assessed. CRIF1 over-expression in mice with collagen-induced arthritis attenuated the clinical and histological signs of inflammatory arthritis. Furthermore, over-expression of CRIF1 in mice with arthritis significantly reduced the number of signal transducer and activator of transcription 3-mediated Th17 cells in the spleen as well as osteoclast differentiation from bone marrow cells. To investigate the impact of loss of CRIF1 in T cells, we generated a conditional CRIF1 gene ablation model using CD4-cre transgenic mice and examined the frequency of Th17 cells and regulatory T cells. Deficiency of CRIF1 in CD4+ cells promoted the production of interleukin-17 and reduced the frequency of regulatory T cells. These results suggest a role for CRIF1 in modulating the activities of Th17 cells and osteoclasts in rheumatoid arthritis.


Assuntos
Artrite Experimental/imunologia , Proteínas de Ciclo Celular/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Animais , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Camundongos Transgênicos
11.
Immunol Lett ; 201: 45-51, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30395870

RESUMO

Inflammatory bowel disease (IBD) is caused by chronic inflammation of the gastrointestinal tract. The pathogenesis of IBD remains unclear. The inflammation is associated with activation of T helper (Th) lymphocytes and chronic production of inflammatory cytokines. Ro60 suppresses the expression of tumor necrosis factor α, interleukin (IL)-6, and interferon α by inhibiting Alu transcription; control of Ro60 mRNA expression may thus be therapeutically useful. However, few studies have evaluated the anti-inflammatory activity of Ro60. The Ro60 level is decreased in IBD patients; we thus hypothesized that Ro60 was involved in the development of this autoimmune disease. We subjected mice with dextran sodium sulfate (DSS)-induced colitis to gene therapy using a vector that overexpressed Ro60 threefold. We scored IBD progression by repeatedly weighing the mice. Ro60 ameliorated colitis severity and reduced the levels of tumor necrosis factor α, IL-6, IL-17, IL-8, and vascular endothelial growth factor. Ro60 overexpression decreased the levels of α-smooth muscle actin (a marker of activated myofibroblasts) and type I collagen. The anti-inflammatory and anti-fibrotic activities of Ro60 ameliorated the severity of DSS-induced colitis in mice by repressing inflammation, fibrosis, angiogenesis, and the production of reactive oxygen species.


Assuntos
Autoantígenos/metabolismo , Colite/imunologia , Colo/patologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , RNA Citoplasmático Pequeno/metabolismo , Ribonucleoproteínas/metabolismo , Actinas/metabolismo , Animais , Autoantígenos/genética , Colite/terapia , Colágeno Tipo I/metabolismo , Colo/fisiologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Fibrose , Terapia Genética , Vetores Genéticos , Humanos , Inflamação/terapia , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/terapia , Camundongos , Camundongos Endogâmicos C57BL , RNA Citoplasmático Pequeno/genética , Ribonucleoproteínas/genética
12.
J Med Food ; 21(8): 745-754, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30110204

RESUMO

Notoginseng Radix and Rehmanniae Radix Preparata have been widely used traditionally for treating inflammatory diseases. This research studies the therapeutic effects of YH23537, the extracts of Notoginseng Radix and Rehmanniae Radix Preparata, on pain and cartilage degeneration in an experimental osteoarthritis (OA) model. Male Wistar rats were inoculated intra-articularly with 3 mg of monosodium iodoacetate (MIA) in the right intra-articular. Four days later, the animals were administrated orally with YH23537 daily for 24 days. Tactile allodynia and weight bearing were measured. Macroscopic and microscopic observations for articular cartilage were performed at the end of the experiment. Protein expression in the joint was determined by immunohistochemistry. The effects of YH23537 on mRNA levels in chondrocytes stimulated with interleukin (IL)-1ß were analyzed using random polymerase chain reaction. OA induction was confirmed by significant decrease of paw withdrawal latency, paw withdrawal threshold, and weight bearing compared with the normal group at 3 days after MIA injection. The YH23537-treated groups displayed significant increases in pain thresholds and weight bearing throughout the observation period. The damage to articular cartilage was significantly lessened visually and histopathologically by YH23537 treatment. YH23537 suppressed the expression of metalloproteinase-3, nitrotyrosine, IL-1ß and IL-6 increased in OA joints. YH23537 upregulated tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 in IL-1ß-stimulated human OA chondrocytes. The protein levels of the NF-κBp65 and HIF-2α in the joint tissues were reduced by YH23537. YH23537 exerted antinociceptive effects and cartilage protective effects in experimental OA rats by suppressing oxidative injury, inflammatory mediators, and inducing anabolic factors. We suggest that YH23537 may have efficacy for treating OA in humans.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças das Cartilagens/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Panax , Extratos Vegetais/farmacologia , Rehmannia , Administração Oral , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Doenças das Cartilagens/induzido quimicamente , Cartilagem Articular/efeitos dos fármacos , Modelos Animais de Doenças , Iodoacetatos , Masculino , Osteoartrite/induzido quimicamente , Medição da Dor , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar
13.
Front Immunol ; 9: 1611, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30042768

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a progressive fibrotic disease that affects the skin and internal organs. Despite evidence implicating increased interleukin-17 (IL-17) activity in SSc, the role of IL-17 in SSc remains uncertain. The purpose of this study was to investigate whether IL-17 plays a pathophysiological role in SSc in two different murine models of SSc. METHODS: Bleomycin (BLM)-induced fibrosis and chronic graft-versus-host disease (cGVHD) models were used. Histological analysis was performed using Masson's trichrome and immunohistochemical staining. Quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunoassays were used to quantify the messenger RNA and protein levels of inflammatory mediators in dermal fibroblasts. RESULTS: IL-1 receptor antagonist-deficient (IL-1Ra-KO) mice were more severely affected by BLM injection, as shown by dermal and pulmonary fibrosis, compared with wild-type (WT) mice. Increased tissue fibrosis was reversed by knocking down IL-17. In vitro experiments showed that IL-1 and IL-17 exerted synergistic effects on the expression of profibrotic and inflammatory mediators. In the cGVHD model, C57BL/6 mice receiving splenocytes of IL-1Ra-KO BALB/c mice developed more severe cGVHD than did those receiving cells from WT mice. Knockdown of IL-17 in IL-1Ra-KO donor mice significantly attenuated the IL-1-induced acceleration of cGVHD severity. CONCLUSION: Targeting IL-1 and its downstream IL-17 activity may be a novel treatment strategy for inhibiting inflammation and tissue fibrosis in SSc.

14.
Front Immunol ; 9: 1525, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034392

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disease caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental factor that affects the development of RA. Metabolites secreted by the gut microbiota maintain homeostasis in the gut through various mechanisms [e.g., butyrate, which is one of the major metabolites of gut microbiota, exerts an anti-inflammatory effect by activating G-protein-coupled receptors and inhibiting histone deacetylases (HDACs)]. Here, we focused on the inhibition of the HDACs by butyrate in RA. To this end, we evaluated the therapeutic effects of butyrate in an animal model of autoimmune arthritis. The arthritis score and incidence were lower in the butyrate-treated group compared to the control group. Also, butyrate inhibited HDAC2 in osteoclasts and HDAC8 in T cells, leading to the acetylation of glucocorticoid receptors and estrogen-related receptors α, respectively. Additionally, control of the TH17/Treg cell balance and inhibition of osteoclastogenesis were confirmed by the changes in target gene expression. Interleukin-10 (IL-10) produced by butyrate-induced expanded Treg cells was critical, as treatment with butyrate did not affect inflammatory arthritis in IL-10-knockout mice. This immune-cell regulation of butyrate was also detected in humans. These findings suggest that butyrate is a candidate agent for the treatment of RA.

15.
Immunol Lett ; 199: 44-52, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29803636

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disease with CD4+ T cell infiltration and hyperplasia of synovial tissues leading to progressive destruction of articular cartilage. In addition to the central role of T cells in the pathogenesis of RA, recent reports have suggested that B cells also contribute to RA. To explore the effects of interleukin (IL)-17 on B cell development and response in excess IL-1 signaling, we generated IL-17 and IL-1 receptor antagonist (IL-1Ra) double-deficient mice via backcrossing IL-17 knockout (KO) and IL-1RaKO mice. We studied the effect of IL-17 deficiency on antibody-producing B cells and regulatory B cells in IL-1RaKO mice. Excess IL-1 signal increased the frequency of B220+ IgG+ cells and plasma cells. It also promoted the production of immunoglobulins in vitro. Moreover, IL-17 deficiency significantly enhanced the frequency of regulatory IL-10-producing regulatory B cells in IL-1RaKO mice. IL-17 deficiency ameliorated disease symptoms of inflammatory arthritis in IL-1RaKO mice by suppressing the frequency of plasma cells and antibody production while enhancing the frequency of IL-10-producing B cells. These findings suggest that IL-17 can trigger an inflammatory immune reaction by activating antibody-producing B cells while suppressing immune regulatory B cells in RA.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos B Reguladores/imunologia , Linfócitos B/imunologia , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/imunologia , Proteína Antagonista do Receptor de Interleucina 1/antagonistas & inibidores , Interleucina-10/imunologia , Interleucina-17/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
16.
Immunol Lett ; 197: 63-69, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29545108

RESUMO

Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that functions in cooperation with various cofactors to regulate gene expression. In the immune system, YY1 enhances cytokine production and T helper (Th) 2 effector cell differentiation, resulting in the activation of inflammation. However, no studies have reported the role of YY1 in Th17 cell regulation, which is implicated in rheumatoid arthritis (RA). We investigated the expression of YY1 in Th17 cells in vitro and revealed increased levels of YY1 mRNA and protein. To elucidate the function of YY1 pathogenesis in RA, we used a collagen-induced arthritis (CIA) mouse model with YY1 deficiency. Deficiency of YY1 reduced the severity of arthritis and joint destruction. Moreover, Th17 cells were dramatically reduced in YY1-deficient mice. The cytokine interleukin (IL)-17 was decreased in YY1-deficient CD4+ T cells ex vivo and in vivo. Interestingly, the level of signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α, IL-17, IL-6, and IL-1ß were markedly decreased in YY1-deficient mice with CIA. The cytokine-inducing function of YY1 was more specific to IL-17 than to interferon-γ. YY1 plays a role in Th17 cell differentiation and RA pathogenesis. Our findings suggest that future RA therapies should target the regulatory mechanism involved in Th17 cell differentiation, in which YY1 may cooperate with the STAT3 signaling pathway.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Inflamação/imunologia , Articulações/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fator de Transcrição YY1/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Imunomodulação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição YY1/genética
17.
J Transl Med ; 16(1): 37, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29466999

RESUMO

BACKGROUND: An altered gut microbiota balance is involved in the pathogenesis of inflammatory bowel disease (IBD), and several probiotic strains are used as dietary supplements to improve intestinal health. We evaluated the therapeutic effect of 12 probiotics in combination with prebiotics, rosavin, and zinc in the dextran sodium sulfate (DSS)-induced colitis mouse model. METHODS: The probiotic complex or the combination drug was administered orally to mice with DSS-induced colitis, and the body weight, disease activity index, colon length, and histopathological parameters were evaluated. Also, the combination drug was applied to HT-29 epithelial cells, and the expression of monocyte chemoattractant protein 1 (MCP-1) was evaluated by real-time polymerase chain reaction. RESULTS: Administration of the combination drug attenuated the severity of DSS-induced colitis. Moreover, the combination drug significantly reduced the levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, IL-1ß, and IL-17, and significantly increased the levels of Foxp3 and IL-10 in colon sections. Additionally, treatment with the combination drug reduced MCP-1 expression in HT-29 cells. Treatment with the combination drug decreased the levels of α-smooth muscle actin and type I collagen compared with vehicle treatment in mice with DSS-induced colitis. CONCLUSION: These results suggest that the combination of a probiotic complex with rosavin, zinc, and prebiotics exerts a therapeutic effect on IBD by modulating production of pro- and anti-inflammatory cytokines and the development of fibrosis.


Assuntos
Colite/tratamento farmacológico , Dissacarídeos/uso terapêutico , Inflamação/tratamento farmacológico , Intestinos/patologia , Prebióticos , Probióticos/uso terapêutico , Zinco/uso terapêutico , Doença Aguda , Animais , Quimiocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Quimioterapia Combinada , Fibrose , Fatores de Transcrição Forkhead/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL
18.
J Med Food ; 21(1): 39-46, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29346060

RESUMO

Probiotic complex, zinc, and coenzyme Q10 (CoQ10) are recognized dietary supplements with an anti-inflammatory role. Although these supplementations are individually known to benefit rheumatoid arthritis (RA), there is no evidence suggesting any synergic effect. The primary goal of this study is to determine whether probiotic complex, zinc, and CoQ10 attenuate the development of collagen-induced arthritis (CIA). The combination of probiotic complex, zinc, and CoQ10 reduced CIA severity by downregulating the levels of IgG, IgG1, and IgG2a in serum. Joint inflammation, bone destruction, and cartilage damage were also improved by the complex. There was a decrease in the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-17, and vascular endothelial growth factor (VEGF) in the joint synovium. The balance between helper T 17 (Th17) cells and regulatory T (Treg) cells was shown to be controlled reciprocally by the complex. These findings suggest that the combination of probiotic complex, zinc, and CoQ10 can ameliorate the development of CIA by inhibiting the expression of proinflammatory cytokines, and is thus an important therapeutic candidate for RA treatment.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Probióticos/administração & dosagem , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Ubiquinona/análogos & derivados , Zinco/administração & dosagem , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Modelos Animais de Doenças , Quimioterapia Combinada , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Ubiquinona/administração & dosagem
19.
Immunol Lett ; 190: 26-33, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28728856

RESUMO

Achaete-scute complex homologue 2 (Ascl2) has been reported to induce the differentiation and activation of follicular helper T (TFH) cells, which are essential for development of Sjögren's syndrome (SS). This study examined whether Ascl2 plays a role in the development of SS. NOD/ShiLtJ mice were injected with an Ascl2-overexpression vector, and the infiltration of lymphocytes into salivary and lacrimal glands was assessed. The expression of inflammatory cytokines and chemoattractants for T or B cells was measured. The activation of TFH cells was assessed using a specific marker of TFH cells. Ascl2 level was also measured in SS patients. Overexpression of Ascl2 increased the expression of C-X-C chemokine receptor type 5 (CXCR5) in both salivary and lacrimal glands (p<0.0001). Overexpression of Ascl2 also increased the expression of proinflammatory cytokines and chemoattractants including interleukin 6 (IL-6), tumor necrosis factor-α, IL-8, programmed cell death 1 (PD-1), IL-21, and B-cell lymphoma 6 (Bcl-6). Overexpression of Ascl2 increased the populations of CD4+CXCR5+, CD4+ICOS+, and CD4+PD-1+ cells. The Ascl2 level was higher in peripheral blood mononuclear cells from SS patients compared with those from healthy controls. Our findings suggest that Ascl2 may play a role in the development and progression of SS and may be a therapeutic target in the treatment of SS.


Assuntos
Linfócitos B/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Aparelho Lacrimal/metabolismo , Glândulas Salivares/metabolismo , Síndrome de Sjogren/genética , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Centro Germinativo/imunologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/metabolismo
20.
Immunol Lett ; 188: 1-8, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28539269

RESUMO

BACKGROUND: Ursodeoxycholic acid (UDCA) has been known that UDCA has prominent effects on liver, however, there is little known about its influence on autoimmune disease. Here, the benefit of UDCA on arthritis rheumatoid (RA) in vivo was tested. METHODS: RA mouse were induced using collagen II (CIA, collagen induced arthritis) where the disease severity or UDCA-related signaling pathway such as AMP-activated protein kinase (AMPK) or small heterodimer partner interacting leucine zipper protein (SMILE) was evaluated by westerblot and immunohistochemical staining. Gene expression was measured by realtime-polymerase chain reaction (PCR). RESULTS: The administration of UDCA effectively alleviated the arthritic score and incidence with decreased cartilage damage and lipid metabolic parameters. UDCA also suppressed the secretion of pro-inflammatory cytokines. It was confirmed that UDCA upregulated the expression of SMILE and transcriptional activity of PPARγ via controlling AMPK or p38 activity. CONCLUSIONS: In the present study, the therapeutic effect of UDCA inducing SMILE through AMPK activation in rheumatoid arthritis mouse as well as other autoimmune disease was proposed.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Ácido Ursodesoxicólico/farmacologia , Animais , Artrite Experimental/diagnóstico , Artrite Experimental/tratamento farmacológico , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Biomarcadores , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Metabolismo dos Lipídeos , Lipídeos/sangue , Masculino , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...