RESUMO
Rheumatoid arthritis (RA) is an autoimmune disease with chronic inflammation, bone erosion, and joint deformation. Synovial tissue in RA patients is full of proinflammatory cytokines and infiltrated immune cells, such as T help (Th) 9, Th17, macrophages, and osteoclasts. Recent reports emphasized a new member of the interleukin (IL)-10 family, IL-26, an inducer of IL-17A that is overexpressed in RA patients. Our previous works found that IL-26 inhibits osteoclastogenesis and conducts monocyte differentiation toward M1 macrophages. In this study, we aimed to clarify the effect of IL-26 on macrophages linking to Th9 and Th17 in IL-9 and IL-17 expression and downstream signal transduction. Murine and human macrophage cell lines and primary culture cells were used and stimulated by IL26. Cytokines expressions were evaluated by flow cytometry. Signal transduction and transcription factors expression were detected by Western blot and real time-PCR. Our results show that IL-26 and IL-9 colocalized in macrophage in RA synovium. IL-26 directly induces macrophage inflammatory cytokines IL-9 and IL-17A expression. IL-26 increases the IL-9 and IL-17A upstream mechanisms IRF4 and RelB expression. Moreover, the AKT-FoxO1 pathway is also activated by IL-26 in IL-9 and IL-17A expressing macrophage. Blockage of AKT phosphorylation enhances IL-26 stimulating IL-9-producing macrophage cells. In conclusion, our results support that IL-26 promotes IL-9- and IL-17-expressing macrophage and might initiate IL-9- and IL-17-related adaptive immunity in rheumatoid arthritis. Targeting IL-26 may a potential therapeutic strategy for rheumatoid arthritis or other IL-9 plus IL-17 dominant diseases.
Assuntos
Artrite Reumatoide , Interleucina-17 , Animais , Humanos , Camundongos , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Interleucina-17/genética , Interleucina-17/farmacologia , Interleucina-17/metabolismo , Interleucina-9/metabolismo , Macrófagos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Th17 , Interleucinas/farmacologiaRESUMO
Type 1 diabetes (T1D) is caused by the destruction of ß cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective treatment for T1D. However, the survival of islet grafts is often disrupted by recurrent autoimmunity. Alpha-lipoic acid (ALA) has been reported to have immunomodulatory effects and, therefore, may have therapeutic potential in the treatment of T1D. In this study, we investigated the therapeutic potential of ALA in autoimmunity inhibition. We treated non-obese diabetic (NOD) mice with spontaneous diabetes and islet-transplantation mice with ALA. The onset of diabetes was decreased and survival of the islet grafts was extended. The populations of Th1 cells decreased, and regulatory T cells (Tregs) increased in ALA-treated mice. The in vitro Treg differentiation was significantly increased by treatment with ALA. The adoptive transfer of ALA-differentiated Tregs into NOD recipients improved the outcome of the islet grafts. Our results showed that in vivo ALA treatment suppressed spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Tregs. Our study also demonstrated the therapeutic potential of ALA in Treg-based cell therapies and islet transplantation used in the treatment of T1D.
Assuntos
Autoimunidade , Diabetes Mellitus Experimental/prevenção & controle , Diabetes Mellitus Tipo 1/prevenção & controle , Transplante das Ilhotas Pancreáticas/métodos , Ilhotas Pancreáticas/citologia , Linfócitos T Reguladores/imunologia , Ácido Tióctico/farmacologia , Animais , Antioxidantes/farmacologia , Diferenciação Celular , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Feminino , Sobrevivência de Enxerto , Camundongos , Camundongos Endogâmicos NOD , Células Th1RESUMO
PURPOSE: Interleukin-1α (IL-1α) is a potent cytokine that plays a role in inflammatory arthritis and bone loss. Decoy receptor 3 (DCR3) is an immune modulator of monocytes and macrophages. The aim of this study was to investigate the mechanism of DCR3 in IL-1α-induced osteoclastogenesis. METHODS: We treated murine macrophages with DCR3 during receptor activator of nuclear factor kappa Β ligand- (RANKL-) plus IL-1α-induced osteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed using a pit formation assay. The mechanisms of inhibition were studied by biochemical analyses, including RT-PCR, immunofluorescent staining, flow cytometry, an apoptosis assay, immunoblotting, and ELISA. RESULTS: DCR3 suppresses IL-1α-induced osteoclastogenesis in both primary murine bone marrow-derived macrophages (BMM) and RAW264.7 cells as it inhibits bone resorption. DCR3 induces RANKL-treated osteoclast precursor cells to express IL-1α, secretory IL-1ra (sIL-1ra), intracellular IL-1ra (icIL-1ra), reactive oxygen species (ROS), and Fas ligand and to activate IL-1α-induced interleukin-1 receptor-associated kinase 4 (IRAK4). The suppression of DCR3 during RANKL- or IL-1α-induced osteoclastogenesis may be due to the abundant secretion of IL-1ra, accumulation of ROS, and expression of Fas ligand in apoptotic osteoclast precursor cells. CONCLUSIONS: We concluded that there is an inhibitory effect of DCR3 on osteoclastogenesis via ROS accumulation and ROS-induced Fas ligand, IL-1α, and IL-1ra expression. Our results suggested that the upregulation of DCR3 in preosteoclasts might be a therapeutic target in inflammatory IL-1α-induced bone resorption.
Assuntos
Proteína Ligante Fas/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/metabolismo , Osteoclastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Membro 6b de Receptores do Fator de Necrose Tumoral/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Morte Celular/genética , Morte Celular/fisiologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Immunoblotting , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Camundongos , Osteoclastos/citologia , Células RAW 264.7 , Fosfatase Ácida Resistente a Tartarato/metabolismoRESUMO
Advanced glycation end products (AGE) and the receptor for AGE (RAGE) have been found to be pivotal biomarkers to predict the risk of inflammation and oxidative stress. Limited evidence focuses on the influence of occupational exposure to polycyclic aromatic hydrocarbon (PAH) and metal fumes on AGE and RAGE in shipyard welders. Our aim was to determine the relationships among PAH, metal exposure, and inflammatory biomarkers. From September 1 to December 31, 2017, 53 welding workers (exposed group) and 29 office workers (control group) were enrolled in the study. Comprehensive workups included demographic characteristics, laboratory data, AGE, RAGE, Interleukin-6 (IL-6), tumor necrosis factor-α, PAH, and urinary metal concentrations. RAGE levels were measured by flow cytometric analysis. Urinary 1-hydroxypyrene (1-OHP) was used as a biomarker of exposure to PAH. Several metals were elevated in the personal fine particulate matter (PM2.5) samples, including Mn, Fe, V, Co, Zn, and Cu. The exposed group had significantly higher exposure to PM2.5 (p = 0.015), RAGE (p = 0.020), IL-6 (p = 0.008) than the control group. After adjusting for pertinent variables, there was still a significant and positive association between Ni level and AGE (ß = 0.101; 95% CI, 0.031-0.172). Significant relationship between Cr and Cd levels and RAGE was observed (ß = 0.173; 95% CI, 0.017-0.329; ß = 0.084; 95% CI, 0.011-0.157, respectively). Participants with elevated 1-OHP level had higher odds of high RAGE level in the model 1 (OR = 3.466, 95% CI, 1.053-11.412) and model 2 (OR = 3.454, 95% CI, 1.034-11.536). The RAGE expression of participants was significantly associated with IL-6 levels in the fully adjusted model (ß = 0.294; 95% CI, 0.083-0.732). Our findings highlighted that urinary metal levels and PAH were associated with increased AGE and RAGE formation in shipyard workers. Elevated serum RAGE might induce the production of proinflammatory cytokines and trigger ensuing inflammatory cascades.
Assuntos
Poluentes Ocupacionais do Ar/análise , Metais/análise , Exposição Ocupacional/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Poluentes Ocupacionais do Ar/toxicidade , Biomarcadores/urina , Gases/análise , Produtos Finais de Glicação Avançada/sangue , Humanos , Inflamação , Masculino , Metais/toxicidade , Estresse Oxidativo , Material Particulado/análise , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Fator de Necrose Tumoral alfa , SoldagemRESUMO
Flaviviruses comprise several medically important viruses, including Japanese encephalitis virus, West Nile virus, dengue virus (DENV), yellow fever virus, and Zika virus (ZIKV). A large outbreak of DENV and ZIKV occurred recently, leading to many cases of illness and death. However, despite decades of effort, we have no clinically specific therapeutic drugs against DENV and ZIKV. Previous studies showed that inflammatory responses play a critical role in dengue and Zika virus pathogenesis. Thus, in this study, we examined a series of novel anti-inflammatory compounds and found that treatment with compound 2d could dose dependently reduce viral protein expression and viral progeny production in HEK-293 and Raw264.7 cells infected with four serotypes of DENV and ZIKV. In addition, considering medication safety, compound 2d could not suppress cyclooxygenase-1 (COX-1) enzymatic activities and thus could prevent the side effect of bleeding. Moreover, compound 2d significantly inhibited COX-2 enzymatic activities and prostaglandin E2 levels, associated with viral replication, compared to results with a selective COX-2 inhibitor, celecoxib. Furthermore, administering 5 mg/kg compound 2d to DENV-2-infected AG129 mice prolonged survival and reduced viremia and serum cytokine levels. Overall, compound 2d showed therapeutic safety and efficacy in vitro and in vivo and could be further developed as a potential therapeutic agent for flavivirus infection.
Assuntos
Anti-Inflamatórios/farmacologia , Dengue/tratamento farmacológico , Infecção por Zika virus/tratamento farmacológico , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Antivirais/administração & dosagem , Antivirais/química , Antivirais/farmacologia , Celecoxib/farmacologia , Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dengue/enzimologia , Dengue/virologia , Vírus da Dengue/classificação , Vírus da Dengue/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Camundongos , Camundongos da Linhagem 129 , Células RAW 264.7 , Segurança , Sorogrupo , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Infecção por Zika virus/enzimologia , Infecção por Zika virus/virologiaRESUMO
Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). This disease leads to intestinal obstruction with or without peritonitis. The imbalance between the populations of Th17 and regulatory T (Treg) cells (higher Th17 cells and lower Treg cells) is part of the pathogenesis of EPS formation. We demonstrated that dimethyl sulfoxide (DMSO) effectively inhibited autoimmune diabetes recurrence in the islet transplantation of NOD mice via the induction of the differentiation of Treg cells. In this study, we investigated the therapeutic potential of DMSO in the inhibition of EPS formation by a mouse model. Under DMSO treatment, the thickening of the parietal and visceral peritoneum was significantly reduced. The populations of CD4, CD8, and IFN-γ-producing CD4 and CD8 T cells were decreased. The populations of IL-4-producing CD4 T lymphocytes, IL-10-producing CD4 T lymphocytes, CD4 CD69 T lymphocytes and Treg lymphocytes were increased. The expression levels of the cytokines IFN-γ, IL-17a, TNF-α and IL-23, in ascites, were significantly decreased following the DMSO treatment. Furthermore, the differentiation of Treg cells was induced by DMSO from naïve CD4 T cells in vitro, and these cells were adoptively transferred into the EPS mice and significantly prevented EPS formation, exhibiting a comparable effect to the in vivo DMSO treatment. We also demonstrated that the differentiation of Treg cells by DMSO occurred via the activation of STAT5 by its epigenetic effect, without altering the PI3K-AKT-mTOR or Raf-ERK pathways. Our results demonstrated, for the first time, that in vivo DMSO treatment suppresses EPS formation in a mouse model. Furthermore, the adoptive transfer of Treg cells that were differentiated from naïve CD4 T cells by an in vitro DMSO treatment exhibited a similar effect to the in vivo DMSO treatment for the prevention of EPS formation.
Assuntos
Dimetil Sulfóxido/imunologia , Fibrose Peritoneal/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Citocinas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Interleucina-17/imunologia , Transplante das Ilhotas Pancreáticas/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Fosfatidilinositol 3-Quinases/imunologia , Células Th17/imunologiaRESUMO
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease of unknown etiology. It is characterized by the presence of rheumatoid factor and anticitrullinated peptide antibodies. The orchestra of the inflammatory process among various immune cells, cytokines, chemokines, proteases, matrix metalloproteinases (MMPs), and reactive oxidative stress play critical immunopathologic roles in the inflammatory cascade of the joint environment, leading to clinical impairment and RA. With the growing understanding of the immunopathogenic mechanisms, increasingly novel marked and potential biologic agents have merged for the treatment of RA in recent years. In this review, we focus on the current understanding of pathogenic mechanisms, highlight novel biologic disease-modifying antirheumatic drugs (DMRADs), targeted synthetic DMRADs, and immune-modulating agents, and identify the applicable immune-mediated therapeutic strategies of the near future. In conclusion, new therapeutic approaches are emerging through a better understanding of the immunopathophysiology of RA, which is improving disease outcomes better than ever.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/terapia , Imunomodulação , Inflamação/terapia , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Quimiocinas/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/imunologia , Fator Reumatoide/imunologiaRESUMO
AIMS/HYPOTHESIS: The relative contribution of T helper (Th)1 and Th17 cells in graft rejection is inconclusive, on the basis of evidence provided by different T cell-related cytokine-deficient animal models and graft types. METHODS: We used novel antigen-presenting-cell-specific Il-12p35 (also known as Il12a)-knockout (KO), IL-23p19-knockdown (KD) and IL-27p28-KD strategies to investigate T cell differentiation in islet graft rejection. RESULTS: In vitro dendritic cell-T cell coculture experiments revealed that dendritic cells from Il-12p35-KO and IL-23p19-KD mice showed reduced ability to stimulate IFN-γ and IL-17 production in T cells, respectively. To further explore the T cell responses in islet graft rejection, we transplanted islets into streptozotocin-induced diabetic NOD/severe combined immunodeficiency (SCID) recipient mice with IL-12-, IL-23-, or IL-27-deficient backgrounds and then challenged them with NOD.BDC2.5 T cells. The survival of islet grafts was significantly prolonged in Il-12p35-KO and IL-23p19-KD recipients compared with the control recipients. T cell infiltrations and Th1 cell populations were also decreased in the grafts, correlating with prolonged graft survival. CONCLUSIONS/INTERPRETATION: Our results suggest that IL-12 and IL-23 promote and/or maintain Th1 cell-mediated islet graft rejection. Thus, blockade of IL-12 and IL-23 might act as therapeutic strategies for reducing rejection responses.
Assuntos
Interleucina-12/metabolismo , Transplante das Ilhotas Pancreáticas/imunologia , Animais , Autoimunidade/imunologia , Linfócitos T CD4-Positivos/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Sobrevivência de Enxerto/fisiologia , Imuno-Histoquímica , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Th17/enzimologia , Células Th17/metabolismoRESUMO
BACKGROUND: Danshen is a common traditional Chinese medicine used to treat neoplastic and chronic inflammatory diseases in China. However, the effects of Danshen on human oral cancer cells remain relatively unknown. This study investigated the antiproliferative effects of a Danshen extract on human oral cancer SAS, SCC25, OEC-M1, and KB drug-resistant cell lines and elucidated the possible underlying mechanism. METHODS: We investigated the anticancer potential of the Danshen extract in human oral cancer cell lines and an in vivo oral cancer xenograft mouse model. The expression of apoptosis-related molecules was evaluated through Western blotting, and the concentration of in vivo apoptotic markers was measured using immunohistochemical staining. The antitumor effects of 5-fluorouracil and the Danshen extract were compared. RESULTS: Cell proliferation assays revealed that the Danshen extract strongly inhibited oral cancer cell proliferation. Cell morphology studies revealed that the Danshen extract inhibited the growth of SAS, SCC25, and OEC-M1 cells by inducing apoptosis. The Flow cytometric analysis indicated that the Danshen extract induced cell cycle G0/G1 arrest. Immunoblotting analysis for the expression of active caspase-3 and X-linked inhibitor of apoptosis protein indicated that Danshen extract-induced apoptosis in human oral cancer SAS cells was mediated through the caspase pathway. Moreover, the Danshen extract significantly inhibited growth in the SAS xenograft mouse model. Furthermore, the Danshen extract circumvented drug resistance in KB drug-resistant oral cancer cells. CONCLUSION: The study results suggest that the Danshen extract could be a potential anticancer agent in oral cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Neoplasias Bucais/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Camundongos SCID , Salvia miltiorrhiza , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: Advanced oral cancer is a major public health concern because of a lack of effective prevention and treatment. Triptolide (TPL), a diterpenoid triepoxide derived from the Chinese herb Tripterygium wilfordii, has been demonstrated to possess strong anticancer properties. In this study, we investigated whether TPL exerts anticancer effects on the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Human macrophage-like U937 cells were co-inoculated with oral cancer SAS cells in a noncontact transwell coculture system. Cytokine expression was detected using ELISA, and cell proliferation was detected using methylene blue. RNA levels were detected using qPCR. Protein levels were detected using Western blot analysis. In vivo experiments involved using xenografted NOD/SCID mice. RESULTS: Our results demonstrated that TPL inhibited the growth of SAS cells co-inoculated with U937 cells in vitro and in vivo. TPL inhibited the invasion, migration ability, and angiogenesis of SAS cells co-inoculated with U937 cells. Expression of cytokines IL-6, IL-8, and TNF-α was induced by co-inoculation, but TPL repressed their expression. CONCLUSION: TPL suppressed the expression of cytokines IL-6, IL-8, and TNF-α, as well as tumor growth, invasion, migration, and angiogenesis in the co-inoculation of human tongue cancer cells with macrophage-like U937 cells. CLINICAL RELEVANCE: TPL is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating tumor-associated macrophages in a tumor microenvironment of HNSCC.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Fenantrenos/farmacologia , Células U937 , Animais , Western Blotting , Carcinoma de Células Escamosas/tratamento farmacológico , Técnicas de Cocultura , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Compostos de Epóxi/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Reação em Cadeia da Polimerase , Microambiente TumoralRESUMO
OBJECTIVE: IL-26 has been shown to have high expression in RA. However, the effects of IL-26 on bone destruction in RA have not been evaluated. The aim of this study was to investigate the effects and mechanisms of IL-26 on RANK ligand (RANKL)-induced osteoclastogenesis. METHODS: We treated cells with IL-26 in RANKL-induced oseteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed by pit formation assay and F-actin ring formation. The mechanism of the inhibition was studied by biochemical analyses such as RT-PCR, immunofluorescence staining and immunoblotting. In addition, cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: IL-26 inhibited RANKL-induced TRAP-positive multinucleated cells and inhibited RANKL-induced nuclear factor κB (NF-κB) activation and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) nuclear translocation in RAW264.7 cells. Also, IL-26 significantly inhibited the bone-resorbing activity and F-actin ring formation ability of mature osteoclasts. Moreover, IL-26 suppressed RANKL-induced mitogen-activated protein kinase activation and NFATc1 downstream gene expression. CONCLUSION: We suggest that the inhibitory activity of IL-26 on osteoclastogenesis is via down-regulation of RANKL-induced NF-κB and NFATc1 expression. Our results suggest IL-26 as a possible new remedy against osteolytic bone destruction.
Assuntos
Interleucinas/fisiologia , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteogênese/fisiologia , Animais , Artrite Reumatoide/fisiopatologia , Reabsorção Óssea/fisiopatologia , Regulação para Baixo , Humanos , Camundongos , Osteoclastos/fisiologia , Osteólise/fisiopatologia , Ligante RANK/metabolismo , Células RAW 264.7RESUMO
OBJECTIVES: Death domain-associated protein (Daxx) has been recently implicated as a positive factor in ovarian cancer and prostate cancer, but the role of Daxx in oral squamous cell carcinoma (OSCC) has never been addressed. Herein, we investigate the expression and function of Daxx in OSCC. MATERIALS AND METHODS: RT-quantitative PCR, Western blotting, and immunohistochemistry were used to evaluation of the expression of Daxx in human OSCC cell lines and clinical surgical specimens. Short hairpin RNA targeting Daxx was transduced by lentivirus infection to knockdown the expression of Daxx in SAS and SCC25 cell lines, and the influence of this knockdown was evaluated by analyzing the growth and the cell cycle in transduced cells. Immunoprecipitation and sequential chromatin immunoprecipitation-quantitative PCR were used to analyze the associations between Daxx, TCF4, and cyclin D1 promoter. Xenograft tumor model was used to evaluate the in vivo tumorigenicity of Daxx in OSCC. RESULTS: Daxx mRNA and protein expression are elevated in several OSCC cell lines and human OSCC samples in comparison to those in normal tissue. We further find that depletion of Daxx decreases OSCC cell growth activity through G1 cell cycle arrest. Daxx silencing reduces cyclin D1 expression via a Daxx-TCF4 interaction, whereas the Daxx depletion-mediated G1 arrest can be relieved by ectopic expression of cyclin D1. Moreover, we show that in OSCC clinical samples, the expression of Daxx is significantly correlated with that of cyclin D1. CONCLUSION: Our data demonstrate the importance of Daxx in regulation of cyclin D1 expression and provide the first evidence that Daxx exhibits tumor-promoting activity in OSCC. CLINICAL RELEVANCE: Daxx plays an important role in malignant transformation of OSCC and may serves as a target for cancer prevention and treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Carcinoma de Células Escamosas/metabolismo , Ciclina D1/metabolismo , Neoplasias Bucais/metabolismo , Proteínas Nucleares/fisiologia , Fatores de Transcrição/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Carcinoma de Células Escamosas/patologia , Ciclo Celular , Linhagem Celular Tumoral , Proteínas Correpressoras , Feminino , Xenoenxertos , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Pessoa de Meia-Idade , Chaperonas Moleculares , Neoplasias Bucais/patologia , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição 4RESUMO
Type 1 diabetes mellitus (T1D) is caused by the destruction of insulin-producing ß cells in pancreatic islets by autoimmune T cells. Islet transplantation has been established as an effective therapeutic strategy for T1D. However, the survival of islet grafts can be disrupted by recurrent autoimmunity. Dimethyl sulfoxide (DMSO) is a solvent for organic and inorganic substances and an organ-conserving agent used in solid organ transplantations. DMSO also exerts anti-inflammatory, reactive oxygen species scavenger and immunomodulatory effects and therefore exhibits therapeutic potential for the treatment of several human inflammatory diseases. In this study, we investigated the therapeutic potential of DMSO in the inhibition of autoimmunity. We treated an animal model of islet transplantation (NOD mice) with DMSO. The survival of the syngeneic islet grafts was significantly prolonged. The population numbers of CD8, DC and Th1 cells were decreased, and regulatory T (Treg) cell numbers were increased in recipients. The expression levels of IFN-γ and proliferation of T cells were also reduced following DMSO treatment. Furthermore, the differentiation of Treg cells from naive CD4 T cells was significantly increased in the in vitro study. Our results demonstrate for the first time that in vivo DMSO treatment suppresses spontaneous diabetes and autoimmune recurrence in NOD mice by inhibiting the Th1 immune response and inducing the differentiation of Treg cells.
Assuntos
Doenças Autoimunes/prevenção & controle , Diabetes Mellitus/prevenção & controle , Dimetil Sulfóxido/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Insulina/metabolismo , Transplante das Ilhotas Pancreáticas , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCIDRESUMO
Advanced oral cancer has a poor prognosis because of the lack of an effective treatment. We explored the efficiency of combined treatment with triptolide and ionizing radiation for treating oral cancer. Human tongue cancer cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation. Cell proliferation, cell cycle arrest, and apoptotic influences were analyzed by FACS and immunohistochemistry. Tumor potency was examined in an in vivo human tongue cancer cells xenograft mouse model. Our results demonstrated that triptolide caused a marked reduction in colony number that was further enhanced with increasing doses of ionizing radiation. Triptolide increased apoptosis and decreased the expression of anti-apoptotic proteins. In vivo, combination treatment synergistically reduced tumor weight and volume possibly via the induction of apoptosis and reduction in anti-apoptotic protein expression. In conclusion, triptolide plus ionizing radiation treatment had synergistic anti-tumor effects, especially in vivo, and may be a promising combined modality therapy for advanced oral cancer.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Diterpenos/uso terapêutico , Fenantrenos/uso terapêutico , Fitoterapia , Neoplasias da Língua/tratamento farmacológico , Tripterygium/química , Animais , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/radioterapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Diterpenos/farmacologia , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Humanos , Camundongos , Fenantrenos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Língua/efeitos dos fármacos , Neoplasias da Língua/radioterapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Encapsulating peritoneal sclerosis (EPS) is a severe complication of peritoneal dialysis (PD). Surgery is a therapeutic strategy for the treatment of complete intestinal obstruction. However, complete intestinal obstruction in long-term PD results in high mortality and morbidity rates after surgery. Immunopathogenesis participates in EPS formation: CD8, Th1, and Th17 cell numbers increased during the formation of EPS. The anti-inflammatory and immunomodulatory effects of melatonin may have beneficial effects on this EPS. In the present study, we determined that melatonin treatment significantly decreases the Th1 and Th17 cell populations in mice with EPS, decreases the production of IL-1ß, TNF-α, IL-6, and IFN-γ, and increases the production of IL-10. The suppression of Th1 and Th17 cell differentiation by melatonin occurs through the inhibition of dendritic cell (DC) activation by affecting the initiation of the NF-κB signaling pathway in DCs. Our study suggests that melatonin has preventive potential against the formation of EPS in patients with PD.
Assuntos
Obstrução Intestinal , Melatonina , Fibrose Peritoneal , Humanos , Animais , Camundongos , Fibrose Peritoneal/etiologia , NF-kappa B/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Diferenciação Celular , Transdução de Sinais , Células Dendríticas/metabolismo , Obstrução Intestinal/complicações , Obstrução Intestinal/patologiaRESUMO
ALA (α-lipoic acid) is a natural, endogenous antioxidant that acts as a PPAR-γ (peroxisome-proliferator-activated receptor-γ) agonist to counteract oxidative stress. Thus far, the antioxidative and immunomodulatory effects of ALA on EAE (experimental autoimmune encephalomyelitis) are not well understood. In this study, we found that ALA restricts the infiltration of inflammatory cells into the CNS (central nervous system) in MOG (myelin oligodendrocyte glycoprotein)-EAE mice, thus reducing the disease severity. In addition, we revealed that ALA significantly suppresses the number and percentage of encephalitogenic Th1 and Th17 cells and increases splenic Treg-cells (regulatory T-cells). Strikingly, we further demonstrated that ALA induces endogenous PPAR-γ centrally and peripherally but has no effect on HO-1 (haem oxygenase 1). Together, these data suggest that ALA can up-regulate endogenous systemic and central PPAR-γ and enhance systemic Treg-cells to inhibit the inflammatory response and ameliorate MOG-EAE. In conclusion, our data provide the first evidence that ALA can augment the production of PPAR-γ in vivo and modulate adaptive immunity both centrally and peripherally in EAE and may reveal further antioxidative and immunomodulatory mechanisms for the application of ALA in human MS (multiple sclerosis).
Assuntos
Antioxidantes/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , PPAR gama/efeitos dos fármacos , Ácido Tióctico/uso terapêutico , Animais , Antioxidantes/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Heme Oxigenase-1/biossíntese , Heme Oxigenase-1/efeitos dos fármacos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , PPAR gama/biossíntese , Baço/imunologia , Baço/transplante , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Ácido Tióctico/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease.
Assuntos
Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/etiologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Melatonina/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Melatonina/biossínteseRESUMO
Acute lung injury (ALI) is characterised by severe pulmonary inflammation, alveolar-capillary barrier disruption, and pulmonary oedema. Therefore, establishing effective therapeutic targets for ALI prevention is crucial. The present study reports a novel function of RNF128 in regulating LPS-induced ALI. Severe lung damage and increased immune cell infiltration were detected in RNF128-deficient mice. In vitro experiments revealed that RNF128 inhibits neutrophil activation by binding to myeloperoxidase (MPO) and reducing its levels and activity. Moreover, RNF128 regulates alveolar macrophage activation and neutrophil infiltration by interacting with TLR4, targeting it for degradation, and inhibiting NF-κB activation, hence decreasing pro-inflammatory cytokines. Our results demonstrate for the first time that RNF128 is a negative regulator of MPO and TLR4 in neutrophils and alveolar macrophages, respectively. However, AAV9-mediated RNF128 overexpression alleviated lung tissue damage and reduced inflammatory cell infiltration. Thus, RNF128 is a promising therapeutic candidate for pharmacological interventions in ALI.
Assuntos
Lesão Pulmonar Aguda , NF-kappa B , Ubiquitina-Proteína Ligases , Animais , Camundongos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/prevenção & controle , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Infiltração de Neutrófilos , NF-kappa B/metabolismo , Peroxidase/metabolismo , Receptor 4 Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The dysregulated expression of cyclin genes can lead to the uncontrolled proliferation of cancer cells. Histone demethylase Jumonji-C domain-containing protein 5 (KDM8, JMJD5) and cyclin A1 (CCNA1) are pivotal in cell cycle progression. A promising candidate for augmenting cancer treatment is Allyl isothiocyanate (AITC), a natural dietary chemotherapeutic and epigenetic modulator. This study aimed to investigate AITC's impact on the KDM8/CCNA1 axis to elucidate its role in oral squamous cell carcinoma (OSCC) tumorigenesis. The expression of KDM8 and CCNA1 was assessed using a tissue microarray (TMA) immunohistochemistry (IHC) assay. In vitro experiments with OSCC cell lines and in vivo experiments with patient-derived tumor xenograft (PDTX) and SAS subcutaneous xenograft tumor models were conducted to explore AITC's effects on their expression and cell proliferation. The results showed elevated KDM8 and CCNA1 levels in the OSCC patient samples. AITC exhibited inhibitory effects on OSCC tumor growth in vitro and in vivo. Additionally, AITC downregulated KDM8 and CCNA1 expression while inducing histone H3K36me2 expression in oral cancer cells. These findings underscore AITC's remarkable anticancer properties against oral cancer, highlighting its potential as a therapeutic option for oral cancer treatment by disrupting the cell cycle by targeting the KDM8/CCNA1 axis.
RESUMO
Idiopathic membranous nephropathy (MN), an autoimmune-mediated glomerulonephritis, is one of the most common causes of nephrotic syndrome in adults. Therapeutic agents for MN remain ill defined. We assessed the efficacy of melatonin therapy for MN. Experimental murine MN was induced with cationic bovine serum albumin, and the mice were immediately administered 20 mg/kg melatonin or phosphate-buffered saline subcutaneously once a day. Disease severity was verified by examining serum and urine metabolic profiles and renal histopathology. The expression of cytokines and oxidative stress markers, cell apoptosis, and the associated mechanisms were also determined. Mice treated with melatonin displayed a significant reduction in proteinuria and a marked amelioration of glomerular lesions, with attenuated immunocomplex deposition. The subpopulations of T cells were not altered, but the CD19(+) B-cell subpopulation was significantly reduced in the MN mice treated with melatonin. The expression of cytokine mRNAs in splenocytes indicated that melatonin reduced the expression of proinflammatory cytokines and increased the expression of anti-inflammatory cytokines (interleukin 10). The production of reactive oxygen species and TUNEL-positive apoptotic cells in the kidney were also significantly reduced in the melatonin-treated MN mice. Melatonin also upregulated heme oxygenase 1 (HO1) and ameliorated MN. The blockade of HO1 expression with SnPP, a HO1 inhibitor, attenuated HO1 induction by melatonin and thus mitigated its renoprotective effects during MN. Our results suggest that melatonin treatment ameliorates experimental MN via multiple pathways, including by its antioxidative, antiapoptotic, and immunomodulatory effects. Melatonin should be considered a potential therapeutic intervention for MN in the future.