Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 572
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Histochem ; 63(4)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31833328

RESUMO

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by interleukin (IL)-6 and IL-10 that generate nearly opposing responses. The suppressor of cytokine signaling 3 (SOCS3) is the negative regulator of STAT3 and plays an important role in the negative regulation of the inflammatory process. Evidence has shown the importance of STAT3 and SOCS3 during implantation and normal pregnancy. However, little is known about the relationship of both factors under hyperglycemic condition. The aim of this study was to evaluate the placenta regions exhibiting immunopositivity for STAT3 and SOCS3 in hyperglycemic rats, as well as correlate these proteins with IL-10 and IL-6 levels. It was observed increased expression of STAT3 at the labyrinth (approximately 47% of increase compared to control) and junctional zone (approximately 32% of increase compared to control) from hyperglycemic placentas. Similar results were observed to SOCS3 (approximately 71% -labyrinth- and 53% -junctional zone- of increase compared to control). The levels of IL-10 were augmented at hyperglycemic placentas (approximately 1.5 fold of increase) and they were positively correlated with the increase of STAT3 at the labyrinth and SOCS at junctional zone. Therefore, under hyperglycemic conditions, the relation between STAT3 and SOCS3 was changed, leading to unbalance of the cytokine profile.


Assuntos
Hiperglicemia/metabolismo , Placenta/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Animais , Anticorpos/imunologia , Feminino , Cabras , Hiperglicemia/patologia , Imuno-Histoquímica , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Placenta/patologia , Gravidez , Coelhos , Ratos Wistar , Fator de Transcrição STAT3/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia
2.
Blood ; 134(13): 1084-1094, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31409670

RESUMO

Coculture of nurse-like cells (NLCs) with chronic lymphocytic leukemia (CLL) cells induced leukemia cell phosphorylation of STAT3 (pSTAT3), which could be blocked by anti-Wnt5a antibodies or the anti-ROR1 monoclonal antibody, cirmtuzumab. Time-course studies revealed Wnt5a could induce activation of NF-κB within 30 minutes, but required more than 3 hours to induce pSTAT3. Culture of isolated CLL cells for 24 hours revealed Wnt5a-induced expression of interleukin 6 (IL-6), IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn could induce pSTAT3 in unstimulated CLL cells within 30 minutes. We found that Wnt5a could induce CLL cell expression of NF-κB target genes, including IL-6, and that this effect could be blocked by cirmtuzumab or drugs that inhibit NF-κB. Examination of CLL cells and plasma collected from patients treated with cirmtuzumab revealed reduced levels of phosphorylated p65 and diminished expression of NF-κB and STAT3 target genes in CLL cells, as well as lower plasma levels of IL-6, in the samples after therapy. Collectively, these studies indicate that Wnt5a/ROR1-dependent signaling contributes to CLL cell activation of NF-κB, which in turn causes autocrine IL-6-induced activation of pSTAT3. As such, this study demonstrates that cirmtuzumab can inhibit leukemia cell activation of both NF-κB and STAT3 in patients with CLL.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos Imunológicos/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , NF-kappa B/imunologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/imunologia , Proteína Wnt-5a/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Fator de Transcrição STAT3/imunologia , Células Tumorais Cultivadas
3.
J Agric Food Chem ; 67(36): 10069-10078, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31422663

RESUMO

Macrophage polarization has been implicated in the pathogenesis of obesity and type 2 diabetes, which are recognized as chronic proinflammatory diseases. This study investigated that high level of glucose, similar to lipopolysaccharide (LPS), activated macrophages toward M1 phenotypes and 1-20 µM asaronic acid (AA) counteracted diabetic macrophage activation. AA reduced the LPS-promoted secretion of proinflammatory interleukin (IL)-6 and monocyte chemoattractant protein-1. The LPS markedly elevated the macrophage induction of the M1 markers of Toll-like receptor 4 (TLR4), CD36, and CD68, which was attenuated by AA. Also, the LPS significantly enhanced the nuclear factor (NF)-κB transactivation, signal transducers, and activators of transcription 1 (STAT1)/STAT3 activation and suppressor of cytokine signaling 3 (SOCS3) induction in macrophages. However, AA highly suppressed the aforementioned effects of LPS. Glucose-stimulated macrophages expressed advanced glycation end products (AGEs) and receptor for AGE (RAGE). Administration of 20 µM AA to macrophages partly but significantly attenuated such effects (1.65 ± 0.12 vs 0.95 ± 0.25 times glucose control for AGE; 2.33 ± 0.31 vs 1.40 ± 0.22 times glucose control for RAGE). Furthermore, glucose enhanced the macrophage induction of TLR4 and inducible nitric oxide synthase and IL-6 production, while it demoted the production of anti-inflammatory arginase-1 and IL-10. In contrast, AA reversed the induction of these markers in glucose-loaded macrophages. AA dose-dependently and significantly encumbered NF-κB transactivation, Janus kinase 2 (JAK2) and STAT1/STAT3 activation, and SOCS3 induction upregulated in glucose-supplemented macrophages. These results demonstrated for the first time that AA may limit diabetic macrophage activation toward the M1 phenotype through the inhibition of TLR4-/IL-6-mediated NF-κB/JAK2-STAT signaling entailing AGE-RAGE interaction.


Assuntos
Glucose/imunologia , Janus Quinase 2/imunologia , Macrófagos/efeitos dos fármacos , NF-kappa B/imunologia , Extratos Vegetais/farmacologia , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/imunologia , Animais , Linhagem Celular , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinase 2/genética , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , Perilla/química , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética
4.
Nat Commun ; 10(1): 3471, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31375662

RESUMO

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-ß-related gene signature in mice. We also report elevated levels of IFN-ß in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-ß impairs, whereas treatment with exogenous IFN-ß enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-ß promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-ß produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation.


Assuntos
Interferon beta/metabolismo , Macrófagos/imunologia , Peritonite/imunologia , Pneumonia Bacteriana/imunologia , Adulto , Idoso , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Escherichia coli/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Interferon beta/genética , Interferon beta/imunologia , Células Jurkat , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neutrófilos , Pneumonia Bacteriana/microbiologia , Cultura Primária de Células , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo
5.
Nat Commun ; 10(1): 3320, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346169

RESUMO

Activation of macrophage proinflammatory and antimicrobial phenotypes is regulated by IFN-γ and LPS via synergistic induction of canonical, inflammatory NF-κB target genes. However, whether IFN-γ negatively regulates components of the LPS response, and how this may affect macrophage activation, is still unclear. Here we use combined transcriptomic and epigenomic approaches to find that IFN-γ selectively abrogates LPS-induced feedback and alters macrophage metabolic pathways by suppressing TLR4-mediated gene activation. In contrast to superinduction of inflammatory genes via enhancers that bind IRF1 and STAT1, IFN-γ represses target enhancers that bind STAT3. TLR4-activated but IFN-γ-suppressed enhancers comprise two subsets discernable by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin. Our findings thus show that IFN-γ suppresses feedback inhibitory and metabolic components of TLR responses to enhance macrophage activation; they also provide insights for IFN-γ-mediated selective inhibition of TLR4-induced transcription. Such inhibition can contribute to severe and sustained inflammatory responses.


Assuntos
Interferon gama/imunologia , Macrófagos/imunologia , Receptor 4 Toll-Like/imunologia , Regulação da Expressão Gênica , Humanos , Lipopolissacarídeos/imunologia , Ativação de Macrófagos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Receptor 4 Toll-Like/genética
6.
Pediatr Hematol Oncol ; 36(4): 198-210, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31287345

RESUMO

The pathogenesis of aplastic anemia (AA) in children is not clear. This study was conducted to investigate the changes in the proportion and function of regulatory T cells (Tregs) in pediatric AA. The proportion of Tregs, mRNA levels of transcription factors, and concentrations of cytokines were measured by flow cytometry, reverse transcription-PCR, and enzyme-linked immunosorbent assay, respectively. Tregs were co-cultured with effector T cells (Teff) to evaluate the function of Tregs. The proportion of Tregs after immunosuppressive therapy (IST) in pediatric AA was monitored dynamically. Compared to the control, the proportions of Tregs in peripheral blood and bone marrow lymphocytes of the untreated AA group were lower (1.31% ± 0.73% vs. 3.16% ± 0.92%, 1.49% ± 0.81% vs. 3.06% ± 0.82%, respectively, p < 0.001). The mRNA levels of FOXP3 and STAT3 in the AA group were lower (p = 0.014; p < 0.001). However, the mRNA levels of T-BET did not significantly differ between groups. The concentration of interferon-γ and interleukin-17 in the AA group were higher (p = 0.004; p = 0.003), whereas the concentration of TGF-ß decreased (p = 0.044). The immunosuppressive function of Tregs was impaired in the AA group. After IST, the proportion of Tregs was significantly lower than that in the control. The proportion of Tregs at the time of diagnosis in the nonresponsive group was lower than that in the responsive group, but the difference was not significant. Treg levels were significantly decreased and were functionally impaired at the time of diagnosis of pediatric AA. However, there was no significant change in Tregs at the resolution of AA.


Assuntos
Anemia Aplástica/imunologia , Células da Medula Óssea/imunologia , Linfócitos T Reguladores/imunologia , Anemia Aplástica/patologia , Células da Medula Óssea/patologia , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Proteínas de Neoplasias/imunologia , RNA Mensageiro/imunologia , Fator de Transcrição STAT3/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/patologia
7.
J Neuroinflammation ; 16(1): 123, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176371

RESUMO

BACKGROUND: Astrocyte activation is a common pathological feature in many brain diseases with neuroinflammation, and revealing the underlying mechanisms might shed light on the regulatory processes of the diseases. Recently, soluble epoxide hydrolase (sEH) has been proposed to affect neuroinflammation in brain injuries. However, the roles of astrocytic sEH in brains with neurodegeneration remain unclear. METHODS: The expression of astrocytic sEH in the brains of APPswe/PSEN1dE9 (APP/PS1) mice developing Alzheimer's disease (AD)-like pathology was evaluated by confocal imaging. LPS-activated primary astrocytes with mRNA silencing or overexpression of sEH were used to investigate its regulatory roles in astrocyte activation and the induction of pro-inflammatory markers. Primary astrocytes isolated from a sEH knockout (sEH-/-) background were also applied. RESULTS: The immunoreactivity of sEH was increased in activated astrocytes in parallel with the progression of AD in APP/PS1 mice. Our data from primary astrocyte cultures further demonstrate that the overexpression of sEH ameliorated, while the silencing of sEH mRNA enhanced, the lipopolysaccharides (LPS)-induced expression of pro-inflammatory markers, such as inducible nitric oxide, cyclooxygenase 2 (COX-2), and pro-inflammatory cytokines. These findings suggest that sEH negatively regulates astrocyte immune responses. Enhanced immune responses found in LPS-activated sEH-/- astrocytes also support the notion that the expression of sEH could suppress the immune responses during astrocyte activation. Similarly, sEH-/- mice that received intraperitoneal injection of LPS showed exacerbated astrocyte activation in the brain, as observed by the elevated expression of glial fibrillary acidic protein (GFAP) and pro-inflammatory markers. Moreover, our data show that the phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was upregulated in activated astrocytes from sEH mouse brains, and the pharmacological blockade of STAT3 activity alleviated the pro-inflammatory effects of sEH deletion in LPS-activated primary astrocytes. CONCLUSIONS: Our results provide evidence, for the first time, showing that sEH negatively regulates astrocytic immune responses and GFAP expression, while the underlying mechanism at least partly involves the downregulation of STAT3 phosphorylation. The discovery of a novel function for sEH in the negative control of astrocytic immune responses involving STAT3 activation confers further insights into the regulatory machinery of astrocyte activation during the development of neurodegeneration.


Assuntos
Astrócitos/imunologia , Epóxido Hidrolases/imunologia , Fator de Transcrição STAT3/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Animais , Astrócitos/metabolismo , Epóxido Hidrolases/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Fator de Transcrição STAT3/metabolismo
8.
Mol Med Rep ; 20(2): 1007-1016, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173202

RESUMO

Inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), has a complex etiology that may be associated with dysbiosis of the microbiota. Previously, our study revealed significant loss of Roseburia intestinalis from the gut of untreated patients with CD, and that R. intestinalis exerted anti­inflammatory functions in TNBS­induced colitis; however, the function of R. intestinalis supernatant is unknown. Therefore, LPS­induced macrophages, including RAW264.7 macrophages and bone marrow­derived macrophages were treated with R. intestinalis supernatant. The results indicated that R. intestinalis supernatant suppressed expression of interleukin (IL)­6 and signal transducer and activator of transcription 3 (STAT3) by macrophages. Additionally, these findings were further verified in vivo in DSS­ and TNBS­induced mouse models of colitis. It was observed that R. intestinalis supernatant ameliorated IBD colitis by reducing the number of inflammatory macrophages and Th17 cells in the colon, and by downregulating the expression of IL­6 and STAT3. Finally, the non­protein components of R. intestinalis supernatant were examined using gas chromatography­mass spectrometry analysis and identified the presence of short­chain fatty acids. In conclusion, the results of the present study indicated that R. intestinalis supernatant may regulate immune responses and ameliorate colitis.


Assuntos
Clostridiales/fisiologia , Colite/terapia , Meios de Cultivo Condicionados/farmacologia , Imunidade Inata/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Clostridiales/química , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Meios de Cultivo Condicionados/química , Sulfato de Dextrana/administração & dosagem , Ácidos Graxos Voláteis/química , Ácidos Graxos Voláteis/isolamento & purificação , Regulação da Expressão Gênica , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/imunologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Células RAW 264.7 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais , Células Th17 , Ácido Trinitrobenzenossulfônico/administração & dosagem
9.
Int Immunopharmacol ; 74: 105677, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177018

RESUMO

Systemic lupus erythematosus (SLE) is a chronic, devastating autoimmune disorder associated with severe organ damage. Recently, the role of Signal Transducer and Activator of Transcription 3 (STAT3) in murine lupus has been described, suggesting the involvement of STAT3 signaling in the development of SLE. Cryptotanshinone (CTS) is an effective inhibitor of STAT3; however its potential as a SLE treatment remains to be explored. To determine the function of CTS in SLE, we treated MRL/lpr female mice with CTS. Firstly, we found CTS treatment reversed the elevated STAT3 signaling of spleens in lupus-prone MRL/lpr mice, accompanying with a dramatically decreased number of T cells, especially double-negative (DN) T cells. Further research showed that CTS inhibited T cell proliferation via suppressing of STAT3 activation in vitro and in vivo. Consistently, we also proved that CTS treatment significantly alleviated autoimmune response including notably diminished skin lesions, reduced spleen size and increased life span. In addition, CTS treatment decreased the levels of auto-antibodies and pro-inflammatory cytokines, as well as normalized structure and function of kidneys. All these data suggested that CTS treatment depressed STAT3 phosphorylation, which resulted in blocked DN T cell proliferation and finally attenuated the spontaneous SLE development. Taken together, our data identify CTS as a potential therapeutic drug for SLE patients.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Fenantrenos/farmacologia , Fenantrenos/uso terapêutico , Linfócitos T/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Citocinas/genética , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , Fator de Transcrição STAT3/imunologia , Linfócitos T/imunologia
10.
Int Immunopharmacol ; 73: 539-551, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177080

RESUMO

OBJECTIVE: We aimed to investigate the immunologic mechanisms by which arsenic trioxide (As2O3) may inhibit T helper 17 (Th17) cell differentiation while promoting regulatory T (Treg) cell generation by modulating signal transducer and activator of transcription 3 (STAT3) in treatment-naïve rheumatoid arthritis (RA) patients. METHODS: Naïve CD4+T cells isolated by fluorescence-activated cell sorting from treatment-naïve RA patients and healthy controls were used to investigate the effect of As2O3 on the process of polarization and the related cytokines. STAT3 transfection experiments were conducted with small interfering RNA (siRNA) and lentivirus STAT3 to verify the mechanism of As2O3 on Th17-Treg balance in vitro. A collagen-induced arthritis (CIA) model was used to detect the clinical scores, histopathological change, bone destruction, Th17-Treg proportion and joint tissue immunohistochemistry. RESULTS: We found that As2O3 prevented activated naïve CD4+T-cells from differentiating into Th17 cells and reduced cytokine production by activated Th17 cells by downregulating their signature transcription factors, STAT3 and orphan nuclear receptors. Notably, As2O3 reduced Th17 cells frequency while increasing Treg cells frequency under specific polarizing conditions in treatment-naïve RA patients by transfecting siRNA STAT3 and lentivirus STAT3. Furthermore, we noticed that applying As2O3 in the CIA model attenuated the infiltration of joint inflammation and bone destruction, and significantly improved the imbalanced Treg-Th17 ratio. CONCLUSIONS: These data indicate that As2O3 may be a potential immune modulator for treatment-naïve RA patients that helps to balance of Treg and Th17 cells through modulating STAT3.


Assuntos
Trióxido de Arsênio/farmacologia , Artrite Reumatoide/imunologia , Fatores Imunológicos/farmacologia , Fator de Transcrição STAT3/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Animais , Trióxido de Arsênio/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Citocinas/imunologia , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Baço/efeitos dos fármacos , Baço/imunologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
11.
Environ Toxicol ; 34(10): 1114-1120, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231976

RESUMO

The aim of this study was designed to investigate the effects of rhynchophyllin (RH) on neuroinflammation in Tourette syndrome (TS) rats. TS model was established in rats by the injection of selective 5-HT2A/2C agonist 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Behavior in DOI-induced rats was tested. Inflammatory cytokines levels such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in serum and striatum were detected. The expression levels of janus kinase 2 (JAK2)/signal transducer and transcription activator 3 (STAT3) and nuclear factor (NF)-κB pathways in striatum were measured by Western blot. Data indicated that RH can significantly reduce the numbers of nodding experiment of TS rats. RH significantly decreased IL-6, IL-1ß, and TNF-α in serum and striatum of TS rats, with altered expression of P-JAK2, P-STAT3, P-NF-κBp65, and P-IκBα in TS rats, as evidenced by Western blot analysis and immunohistochemistry, suggesting that the regulation of JAK2/STAT3 and NF-κB pathways might be involved in the mechanism of RH on TS.


Assuntos
Corpo Estriado/imunologia , Medicamentos de Ervas Chinesas/administração & dosagem , Janus Quinase 2/imunologia , Oxindois/administração & dosagem , Síndrome de Tourette/tratamento farmacológico , Uncaria/química , Animais , Corpo Estriado/efeitos dos fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Janus Quinase 2/genética , Masculino , NF-kappa B/genética , NF-kappa B/imunologia , Propano/efeitos adversos , Propano/análogos & derivados , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Tourette/induzido quimicamente , Síndrome de Tourette/genética , Síndrome de Tourette/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
12.
Mol Immunol ; 111: 162-171, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063937

RESUMO

B cells have been reported to have a suppressive function in autoimmune diseases, which appears to require an increase of CD11b expression on B cells. However, little is known how CD11b is induced in B cells to play the function. In this study, we found that the high expression of CD11b in B cells occurred not only in the mucosal immune organs, but also in systemically immune organs such as the spleen during dextran sulfate sodium (DSS)-induced colitis. Since the inflammatory lesions in mouse models of inflammatory bowel disease (IBD) were revealed to be significantly hypoxic or even anoxic, the B cells from colitic mice Peyer's patches (PP) were investigated to express higher levels of hypoxia-inducible factor-1α (HIF-1α) than naïve B cells from wildtype (WT) mice. HIF-1α siRNA transfection or HIF-1α protein inhibition led to decreased CD11b expression at both the mRNA and protein levels in vitro. B cells with HIF-1α specific knockdown were then adoptively transferred to Rag-1-/- mice. The result displayed that CD11b expression was decreased in B cells and an exacerbated colitis occurred. The bio-informatics promoter analysis and ChIP assay showed that HIF-1α was the critical transcription factor for CD11b and cooperatively formed a complex with the p-STAT3 homodimers to bind onto hypoxia-responsive element (HRE) regions, which was guaranteed by MEK/ERK pathway activation and IL-10 secretion. In conclusion, our study demonstrated the key function of the hypoxia-associated transcription factor HIF-1α together with p-STAT3 in driving CD11b transcription in B cells and controlling B cell's protective activity in experimental inflammatory bowel disease (IBD).


Assuntos
Linfócitos B/imunologia , Antígeno CD11b/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Doenças Inflamatórias Intestinais/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Animais , Colite/imunologia , Colo/imunologia , Regulação da Expressão Gênica/imunologia , Proteínas de Homeodomínio/imunologia , Imunossupressão/métodos , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/imunologia , RNA Mensageiro/imunologia , Baço/imunologia , Fatores de Transcrição/imunologia
13.
Int Immunopharmacol ; 72: 275-283, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31005037

RESUMO

Candida albicans infection-induced acute lung injury is one of the most prevalent diseases in immunosuppressive individual. Nevertheless, the mechanism by which Candida albicans induced acute lung injury remains unclear. The present study investigated the mechanism by which Candida albicans induced acute lung injury in mice. Mice were randomly divided into four groups and intratracheally injected with 60 µl Candida albicans (106 CFU) or normal saline. Half of the mice were sacrificed at 6 h after Candida albicans. The rest of the mice for survival test were observed until 7 d after Candida albicans. As expected, immunosuppression aggravated Candida albicans-induced acute lung injury and death in mice. Additionally, Candida albicans infection elevated mRNA levels of pro-inflammatory and chemokines in lungs and the levels of IL-6, IL-1ß and IL-17 in serum. Further study showed that Candida albicans promoted nuclear translocation of NF-κB p50 and p65 subunits in pulmonary epithelial cells and interstitial cells. Candida albicans induced pulmonary p38, ERK1/2 and Akt phosphorylation in normal and immunosuppressive mice. Moreover, Candida albicans infection activated pulmonary STAT3 signaling in normal and immunosuppressive mice. Overall, these results suggest that Candida albicans induced acute lung injury and death may be through activating several inflammatory signaling pathways.


Assuntos
Lesão Pulmonar Aguda/imunologia , Candidíase/imunologia , Imunossupressão , Lesão Pulmonar Aguda/etiologia , Animais , Candida albicans , Candidíase/complicações , Ciclofosfamida , Citocinas/sangue , Dexametasona , Inflamação/imunologia , Pulmão/imunologia , Masculino , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais
14.
Inflamm Res ; 68(6): 423-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989239

RESUMO

OBJECTIVE: The heterodimeric IL-12 family member cytokines including, IL-12, IL-23, IL-27, and IL-35 and have multiple roles in regulating innate and adaptive immunity with crucial functions in inflammatory disorders such as psoriasis. Chain pairing promiscuity is a feature of the IL-12 family. Recently, based on murine data, a new family member, IL-39, was proposed, consisting of IL23p19 (shared with IL-23) and EBI3 (shared with IL-27 and IL-35). IL-39 has subsequently been implicated in experimental murine lupus. Given the success of IL-23p19 therapeutic targeting in diseases including psoriasis, it is of great interest to confirm the presence of IL-39 in man. Human IL-39 is yet to be either detected or expressed, which has halted research in this area. METHODS: Using a disulphide-linked human chimera protein composing of IL-23p19 and EBI3 human chains, we stimulated human leukocytes, and analysed cytokine secretion and STAT3 phosphorylation. RESULTS AND CONCLUSION: We report that this cytokine shows no activity in human cells. IL-39 chimera protein failed to induce either IL-6, IL-8, TNF, or IL-17A from leukocytes or STAT3 phosphorylation and thus, remains a 'theoretical cytokine' in humans.


Assuntos
Subunidade p19 da Interleucina-23/imunologia , Interleucinas/imunologia , Leucócitos/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Fator de Transcrição STAT3/imunologia , Humanos , Fosforilação , Multimerização Proteica
15.
Prostate ; 79(9): 1018-1031, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31018021

RESUMO

BACKGROUND: Chemotherapy with Docetaxel (Doc) is efficient in a subset of prostate cancer (PCa) cases; however, most patients ultimately develop resistance to Docetaxel. The tumor immune microenvironment and secreted cytokines play a substantial role in development of resistance to chemotherapy. Our previous study has demonstrated that CD4+ T cells in prostate tumor microenvironment contribute to PCa progression; meanwhile, we found increased CD4+ T-cell infiltration in tumor area after Doc treatment; however, their effects on PCa chemosensitivity remain unclear. Here, we aim to explore the role and mechanisms of CD4+ T cells in PCa chemotherapy sensitivity. METHODS: CD4+ T-cell infiltration in Doc-treated paraffin-embedded specimens from transurethral resection of prostate, radical prostatectomy, or bone metastasis was detected by immunohistochemistry. The castration-resistant PCa cell lines-C4-2 and CWR22RV1, and CD4+ T-cell lines-HH and Molt-3 were used in the coculture system. After coculture with the lymphocytes, PCa cell chemosensitivity was detected by cell counting kit-8, terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, and Western blot analysis. Various cell cytokines were determined by cytokine arrays and reverse-transcription polymerase chain reaction. The recombinant human C-C motif chemokine ligand 5 (CCL5) was added to PCa cells for further confirming its effects and anti-CCL5 antibody was used for neutralization. S3I-201, a signal transducer and activator of transcription 3 (STAT3) inhibitor, was added to the coculture system to detect STAT3 role in chemosensitivity. Tumor xenografts in nude mice were used for confirming effects of CD4+ T cells in vivo study. RESULTS: We found more infiltrated CD4+ T cells in human PCa lesions than in the adjacent noncancerous tissues after Doc treatment. In vitro cell line study confirmed that CD4+ T cells increase the PCa Doc resistance. Quantative polymerase chain reaction and cytokine arrays indicated that after coculture with PCa, CD4+ T cells could secrete large amounts of CCL5. Moreover, CCL5 stimulation enhanced PCa resistance to Doc, and anti-CCL5 antibody could partly reverse this process. We found that CD4+ T cells could activate P-STAT3 signaling via secreting CCL5 and adding a STAT3 inhibitor can reverse the chemoresistance. In vivo mouse model with xenografted 22RV1 cells and CD4+ T cells also confirmed the in vitro results. CONCLUSIONS: Together, our results indicate that infiltrating CD4+ T cells could promote PCa chemotherapy resistance via modulation of the CCL5/STAT3 signaling pathway.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiocina CCL5/imunologia , Docetaxel/farmacologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/imunologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Quimiocina CCL5/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Microambiente Tumoral
16.
J Immunol ; 202(10): 3065-3075, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30979816

RESUMO

Although multidisciplinary treatment is widely applied in colorectal cancer (CRC), the prognosis of patients with advanced CRC remains poor. Immunotherapy blocking of programmed cell death ligand 1 (PD-L1) is a promising approach. Binding of the transmembrane protein PD-L1 expressed by tumor cells or tumor microenvironment cells to its receptor programmed cell death 1 (PD-1) induces immunosuppressive signals and reduces the proliferation of T cells, which is an important mechanism of tumor immune escape and a key issue in immunotherapy. However, the regulation of PD-L1 expression is poorly understood in CRC. Fibroblast growth factor (FGF) receptor (FGFR) 2 causes the tyrosine kinase domains to initiate a cascade of intracellular signals by binding to FGFs and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. In this study, we showed that PD-L1 and FGFR2 were frequently overexpressed in CRC, and FGFR2 expression was significantly associated with lymph node metastasis, clinical stage, and poor survival. In the current study, PD-L1 expression was positively correlated with FGFR2 expression in CRC. Tumor-derived-activated FGFR2 induced PD-L1 expression via the JAK/STAT3 signaling pathway in human CRC cells (SW480 and NCI-H716), which induced the apoptosis of Jurkat T cells. FGFR2 also promoted the expression of PD-L1 in a xenograft mouse model of CRC. The results of our study reveal a novel mechanism of PD-L1 expression in CRC, thus providing a theoretical basis for reversing the immune tolerance of FGFR2 overexpression in CRC.


Assuntos
Antígeno B7-H1/imunologia , Neoplasias Colorretais/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Janus Quinases/imunologia , Proteínas de Neoplasias/imunologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Antígeno B7-H1/genética , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células HCT116 , Humanos , Janus Quinases/genética , Células Jurkat , Metástase Linfática , Proteínas de Neoplasias/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética
17.
Nat Commun ; 10(1): 1463, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931933

RESUMO

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC.


Assuntos
Carcinogênese/genética , Colite/genética , Neoplasias Colorretais/genética , Interleucina-6/imunologia , Receptor X Retinoide alfa/genética , Fator de Transcrição STAT3/imunologia , Animais , Carcinogênese/imunologia , Colite/imunologia , Colite Ulcerativa/imunologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Neoplasias Colorretais/imunologia , Meios de Cultivo Condicionados , Modelos Animais de Doenças , Células HCT116 , Humanos , Inflamação , Macrófagos/imunologia , Camundongos , NF-kappa B/imunologia , Receptor X Retinoide alfa/imunologia , Transdução de Sinais , Sulindaco/análogos & derivados , Sulindaco/farmacologia , Fator 6 Associado a Receptor de TNF/imunologia
18.
Life Sci ; 222: 183-194, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30851337

RESUMO

AIMS: Enhancing the potency of dendritic cells (DCs) by downregulating negative immunoregulatory pathways may provide immunotherapeutic possibilities against candidiasis. MAIN METHODS: In this study, a si-RNA method is used to repress expression of the cytokine signaling-3 suppressor (SOCS3) in murine bone marrow-DCs, and then the maturation of DCs and the subsequent T-cell response after exposure to C. albicans are monitored in vitro. KEY FINDINGS: Along with a higher expression of the DC maturation markers CD40, CD86 and MHC-II, IL-6/STAT3 is markedly upregulated in the SOCS3 siRNA-treated DCs after exposure to C. albicans as compared with control DCs. In response to DCs maturation, CD4+ T cells have an increased expression of Th17 cell markers -- including the retinoic acid-related orphan nuclear hormone receptors γt (RORγt), IL-17A and IL-23R -- and increased release of IL-17. We note that this enhanced Th17 cell differentiation induced by siSOCS3-treated DCs in presence of C. albicans can be partly offset when anti-IL-6 antibody is added into the co-culture. SIGNIFICANCE: As with SOCS1 in our previous report, suppression of SOCS3 alone also has the potential to fully activate DCs maturation. However, while SOCS1 knockdown in DCs during C. albicans infection specifically augments Th1 differentiation, SOCS3 silencing particularly increases Th17 differentiation.


Assuntos
Candida albicans/metabolismo , Células Dendríticas/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Células Th17/metabolismo , Animais , Candida albicans/imunologia , Proliferação de Células/fisiologia , Células Cultivadas , Células Dendríticas/imunologia , Feminino , Inativação Gênica , Imunidade Celular/fisiologia , Interleucina-6/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Células Th17/imunologia
19.
Int Immunopharmacol ; 68: 242-251, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30743078

RESUMO

BACKGROUND: Berberine hydrochloride is one the effective compound among Rhizoma Coptidis, Cortex Phellodendri, and other plants. There are several clinical functions of berberine hydrochloride including anti-inflammation, antitumor and immunoregulatory. However, the anti-inflammatory of berberine hydrochloride in ulcerative colitis is barely understood. In this study, we aimed to explore the effects of berberine hydrochloride on dextran sulfate sodium (DSS)-induced rats model of ulcerative colitis. METHODS: The severity of colitis were measured by body weight, survial rate, colon length and disease activity index (DAI) score. The cytokines expression include IL-1, IL-1ß, IL-4, IL-6, IL-10, IL-12, TNF-α, TGF-ß and IFN-γ were performed by RT-PCR and ELISA. Signaling pathway proteins such as p-STAT3, STAT3, p-NF-κB p65 and NF-κB p65 were analyzed by western blot and immunofluorescence. The proteins expression of tight junction were explored using western blotting and immunohistochemistry. RESULT: Rats were administered berberine hydrochloride showed less weight loss and longer colon length than the DSS-induced group. The expression of IL-1, IL-1ß, IL-6, IL-12, TNF-α, TGF-ß and IFN-γ were suppressed, yet the expression of IL-4 and IL-10 were up-regulated by berberine hydrochloride and sulphasalazine treatment compared to the model group. Meanwhile, treatment with berberine hydrochloride effectively increased the expression of SIgA and decreased the expression of iNOS, MPO, MDA. In terms of the biochemical analyses, the results showed that the expression of p-STAT3 was signifcantly increased, while the expression of p-NF-κB (p65) was suppressed compared to the model group via western blot and immunofluorescence analysis. CONCLUSIONS: Berberine hydrochloride has beneficial effects in UC. The possible mechanism of anti-inflammatory response by berberine hydrochloride may involve in the blocking of the IL-6/STAT3/NF-κB signaling pathway. Collectively, these fndings provide evidence that berberine hydrochloride might be a useful herb medicine and serve as a promising novel therapy in the treatment of UC in humans.


Assuntos
Anti-Inflamatórios/uso terapêutico , Berberina/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Citocinas/imunologia , Sulfato de Dextrana , Modelos Animais de Doenças , Masculino , NF-kappa B/imunologia , Ratos Wistar , Fator de Transcrição STAT3/imunologia
20.
J Biol Chem ; 294(15): 6027-6041, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30782844

RESUMO

Escherichia coli and Klebsiella pneumoniae are opportunistic pathogens that are commonly associated with infections at mucosal surfaces, such as the lung or the gut. The host response against these types of infections includes the release of epithelial-derived antimicrobial factors such as lipocalin-2 (LCN-2), a protein that specifically inhibits the iron acquisition of Enterobacteriaceae by binding and neutralizing the bacterial iron-scavenging molecule enterobactin. Regulation of epithelial antimicrobial responses, including the release of LCN-2, has previously been shown to depend on IL-22, a cytokine produced by innate lymphoid cells type 3 (ILC3) during Enterobacteriaceae infections. However, much remains unknown about the extent to which antimicrobial responses are regulated by IL-22 and how IL-22 regulates the expression and production of LCN-2 in intestinal epithelial cells (IECs). Our study demonstrates how IL-22-induced activation of STAT3 synergizes with NF-κB-activating cytokines to enhance LCN-2 expression in human IECs and elucidates how ILC3 are involved in LCN-2-mediated host defense against Enterobacteriaceae. Together, these results provide new insight into the role of ILC3 in regulating LCN-2 expression in human IECs and could prove useful in future studies aimed at understanding the host response against Enterobacteriaceae as well as for the development of antimicrobial therapies against Enterobacteriaceae-related infections.


Assuntos
Células Epiteliais/imunologia , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Lipocalina-2/imunologia , Linfócitos/imunologia , NF-kappa B/imunologia , Fator de Transcrição STAT3/imunologia , Células Epiteliais/patologia , Escherichia coli/imunologia , Infecções por Escherichia coli/imunologia , Infecções por Escherichia coli/patologia , Feminino , Regulação da Expressão Gênica/imunologia , Células HCT116 , Humanos , Infecções por Klebsiella/imunologia , Infecções por Klebsiella/patologia , Klebsiella pneumoniae/imunologia , Linfócitos/patologia , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA