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1.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Biosci Biotechnol Biochem ; 79(4): 643-51, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25522686

RESUMO

Some oligosaccharides have immunoregulatory and anti-inflammatory functions in the intestine. This study investigated the immunoregulatory effect of lactosucrose (LS) on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitic rats. Alkaline phosphatase activity was increased but myeloperoxidase activity was decreased in the LS-TNBS group, as compared with the TNBS group (colitis rats without receiving LS). LS supplementation stimulated IL-4 and IL-10 production, while up-regulating CD86 expression in dendritic cells. LS supplementation reduced the ratio of CD80/CD86 and the ratio of IFN-γ/IL-4 compared to the TNBS group. Moreover, IFN-γ was significantly correlated with CD80 (r = 0.764, p < 0.01), whereas IL-4 was significantly correlated with CD86 (r = 0.489, p < 0.05). These results indicated that LS attenuated colitis by promoting the production of Th2-type cytokines and rebalancing the ratio of Th1/Th2 and that enhanced IL-4 production is correlated with enhanced CD86 expression in the gut. Therefore, LS is a functional food for patients with inflammatory bowel disease.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antígeno B7-2/genética , Colite/tratamento farmacológico , Equilíbrio Th1-Th2/efeitos dos fármacos , Trissacarídeos/farmacologia , Fosfatase Alcalina/genética , Fosfatase Alcalina/imunologia , Animais , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Antígeno B7-2/agonistas , Antígeno B7-2/imunologia , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Feminino , Regulação da Expressão Gênica , Inflamação/prevenção & controle , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/agonistas , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Peroxidase/genética , Peroxidase/imunologia , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Ácido Trinitrobenzenossulfônico
3.
Genet Mol Res ; 13(3): 4932-9, 2014 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-25062480

RESUMO

Infection is the leading risk factor of liver transplantation-related death. Aspergillosis is a life-threatening complication in immune-compromised patients, and is the cause of approximately 2/3 of deaths in liver transplant recipients. In our previous studies, we found a regulatory T cell (Treg) population that showed significantly increased immune tolerance in Aspergillus-infected liver transplant recipients. Furthermore, interleukin (IL)-17 production was also increased, and an IL-17-producing Treg cell subset was identified in these patients. Functional studies of the role of these IL-17-producing Treg cells in the induction of immune tolerance are needed to help reduce the death rate of liver transplantation recipients. This study included 75 liver transplant recipients with and without histologically confirmed aspergillosis after liver transplantation. The percentage of T cell population subsets producing cytokines was detected by fluorescence-activated cell sorting and enzyme-linked immunosorbent assay in peripheral blood. Complements in blood serum were also examined. The risk of acute rejection was lower in Aspergillus-infected liver transplant recipients compared to the non-Aspergillus-infected group; the CD4(+)CD25(hi) T cell population in peripheral blood was higher and the CD4(+)CD45RA-CD45RO(+) T cell population was lower. There was no significant difference between the CD4(+)CD25(lo)CD45RA(+) and CD4(+)CD25(lo)CD45RA- T cell populations. Moreover, IL-6 decreased and IL-4 increased in the blood serum of Aspergillus-infected liver transplant recipients. Together, these results indicate that the incidence of graft rejection in liver transplantation recipients with Aspergillus infections was lower than that of the non-infected group, and suggests a mechanism for this effect.


Assuntos
Aspergilose/imunologia , Aspergillus/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Fígado , Subpopulações de Linfócitos T/imunologia , Adulto , Aspergilose/microbiologia , Antígenos CD4/genética , Antígenos CD4/imunologia , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-4/agonistas , Interleucina-4/biossíntese , Interleucina-4/sangue , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Interleucina-6/sangue , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/imunologia , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Fígado/cirurgia , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/microbiologia
4.
J Immunol ; 183(10): 6657-66, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19880446

RESUMO

Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR(-/-) mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.


Assuntos
Hepatite/imunologia , Células T Matadoras Naturais/imunologia , Osteopontina/imunologia , Receptores Citoplasmáticos e Nucleares/imunologia , Doença Aguda , Animais , Ácidos e Sais Biliares/imunologia , Ácidos e Sais Biliares/metabolismo , Linhagem Celular , Concanavalina A/farmacologia , Hepatite/genética , Hepatite/metabolismo , Interferon gama/agonistas , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/agonistas , Interleucina-4/imunologia , Interleucina-4/metabolismo , Fígado/imunologia , Fígado/patologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitógenos/farmacologia , Células T Matadoras Naturais/metabolismo , Osteopontina/agonistas , Osteopontina/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/imunologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Necrose Tumoral alfa/agonistas , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
5.
J Immunol ; 183(10): 6681-8, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19846875

RESUMO

The alpha7 nicotinic acetylcholine receptor (nAChR) was recently described as an anti-inflammatory target in both macrophages and T cells. Its expression by immune cells may explain the epidemiological data claiming a negative link between cigarette smoking and several inflammatory diseases. In this study, we determined the immunological effects of alpha7 nAChR activation by nicotine. Our results indicate that the alpha7 nAChR is expressed on the surface of CD4(+) T cells and that this expression is up-regulated upon immune activation. Nicotine reduced T cell proliferation in response to an encephalitogenic Ag, as well as the production of Th1 (TNF-alpha and IFN-gamma) and Th17 cytokines (IL-17, IL-17F, IL-21, and IL-22). IL-4 production was increased in the same setting. Attenuation of the Th1 and Th17 lineages was accompanied by reduced T-bet (50%) and increased GATA-3 (350%) expression. Overall, nicotine induced a shift to the Th2 lineage. However, alpha7(-/-)-derived T cells were unaffected by nicotine. Furthermore, nicotine reduced NF-kappaB-mediated transcription as measured by IL-2 and IkappaB transcription. In vivo, administration of nicotine (2 mg/kg s.c.) suppressed the severity of CD4(+) T cell-mediated disease experimental autoimmune encephalomyelitis. alpha7(-/-) mice were refractory to nicotine treatment, although disease severity in those animals was reduced, due to impairment in Ag presentation. Accordingly, CD4(+) and CD11b(+) cells infiltration into the CNS, demyelination, and axonal loss were reduced. Our data implicate a role for the alpha7 nAChR in immune modulation and suggest that alpha7 nAChR agonists may be effective in the treatment of inflammatory disorders.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/antagonistas & inibidores , Nicotina/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Fator de Transcrição GATA3/agonistas , Fator de Transcrição GATA3/imunologia , Fator de Transcrição GATA3/metabolismo , Glicoproteínas/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-4/agonistas , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , NF-kappa B/antagonistas & inibidores , NF-kappa B/imunologia , NF-kappa B/metabolismo , Fragmentos de Peptídeos/imunologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/imunologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/imunologia , Medula Espinal/patologia , Proteínas com Domínio T/antagonistas & inibidores , Proteínas com Domínio T/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Receptor Nicotínico de Acetilcolina alfa7
6.
Cell Immunol ; 259(1): 74-81, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19589505

RESUMO

RNA interference (RNAi) is an exciting mechanism for knocking down any target gene in transcriptional level. It is now clear that small interfering RNA (siRNA), a 19-21nt long dsRNA, can trigger a degradation process (RNAi) that specifically silences the expression of a cognate mRNA. Our findings in this study showed that down regulation of CD40 gene expression in dendritic cells (DCs) by RNAi culminated to immune modulation. Effective delivery of siRNA into DCs would be a reasonable method for the blocking of CD40 gene expression at the cell surface without any effect on other genes and cell cytotoxicity. The effects of siRNA against CD40 mRNA on the function and phenotype of DCs were investigated. The DCs were separated from the mice spleen and then cultured in vitro. By the means of Lipofectamine2000, siRNA was delivered to the cells and the efficacy of transfection was estimated by flow cytometry. By Annexine V and Propidium Iodide staining, we could evaluate the transfected cells viability. Also, the mRNA expression and protein synthesis were assessed by real-time PCR and flow cytometry, respectively. Knocking down the CD40 gene in the DCs caused an increase in IL-4 production, decrease in IL-12 production and allostimulation activity. All together, these effects would stimulate Th2 cytokines production from allogenic T-cells in vitro.


Assuntos
Antígenos CD40/genética , Células Dendríticas/imunologia , Interferência de RNA , Animais , Antígenos CD40/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Dendríticas/efeitos dos fármacos , Inativação Gênica/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-12/antagonistas & inibidores , Interleucina-12/biossíntese , Interleucina-12/imunologia , Interleucina-4/agonistas , Interleucina-4/biossíntese , Interleucina-4/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Células Th2/imunologia , Células Th2/metabolismo
7.
Int Immunol ; 21(7): 859-70, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19477915

RESUMO

The role of invariant NKT (iNKT) cells in reactive arthritis is unknown. We explored the functional role of NKT cells in reactive arthritis using an established murine model of Chlamydia trachomatis-induced arthritis (CtIA). CtIA in wild-type and CD1d knockout (KO) mice was induced by intra-articular injection of C. trachomatis. The effect of alpha-galactosylceramide (alpha-GalCer) activation of iNKT cells was investigated by intra-peritoneal administration of alpha-GalCer. Histopathological and phenotypic changes, chlamydial clearance and cytokine and chemokine production in synovial tissue of the knee joint were investigated after onset of the arthritis. The severity of CtIA was significantly increased in CD1d KO mice, which was associated with decrease in bactericidal cytokine IFN-gamma, regulatory cytokines IL-4 and IL-10 and increase in pro-inflammatory chemokines macrophage inflammatory protein-2 (MIP-2) and IFN-gamma-inducible protein-10 (IP-10). Local clearance of the pathogen from the joint was also decreased. Prior treatment of mice with alpha-GalCer, a potent activator of iNKT cells, significantly reduced the severity of CtIA in mice. The amelioration of CtIA was associated with decrease in chlamydial load and induction of cytokines IFN-gamma, IL-4 and IL-10 and significant suppression of MIP-2 and IP-10. Treatment of established CtIA with alpha-GalCer also demonstrated modulation of CtIA and decrease in chlamydial load. These results suggest that iNKT cells are protective against CtIA and alpha-GalCer-activated iNKT cells have an immunoregulatory role not only in preventing the induction of reactive arthritis but also in modulating established disease.


Assuntos
Artrite Experimental/imunologia , Artrite Infecciosa/imunologia , Infecções por Chlamydia/imunologia , Chlamydia trachomatis , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Artrite Experimental/microbiologia , Artrite Experimental/patologia , Artrite Infecciosa/microbiologia , Artrite Infecciosa/patologia , Quimiocina CXCL10/antagonistas & inibidores , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL2/antagonistas & inibidores , Quimiocina CXCL2/imunologia , Quimiocina CXCL2/metabolismo , Infecções por Chlamydia/microbiologia , Galactosilceramidas/farmacologia , Interferon gama/agonistas , Interferon gama/imunologia , Interferon gama/metabolismo , Interferon gama/farmacologia , Interleucina-10/agonistas , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-4/agonistas , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/microbiologia , Fator de Necrose Tumoral alfa/farmacologia
8.
Eur J Immunol ; 39(4): 1046-55, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19266498

RESUMO

IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-gamma rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-gamma production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.


Assuntos
Interferon gama/metabolismo , Interleucina-12/metabolismo , Interleucinas/imunologia , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Células Th2/imunologia , Animais , Feminino , Humanos , Interferon gama/agonistas , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-33 , Interleucina-4/agonistas , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucinas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/metabolismo , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
9.
Curr Opin Investig Drugs ; 3(7): 1011-6, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12186260

RESUMO

A predominance of T-helper 1 (Th1) activity and a lack of Th2 activity has been documented in the inflamed joints of patients with rheumatoid arthritis (RA). This imbalance is suggested to contribute to activation of, particularly, inflammatory macrophages and B-cells. Th2-mediated immunity, like atopy, is associated with amelioriated inflammation and joint damage in RA patients. Despite the potent anti-inflammatory capacities of two prominent Th2 cytokines in many experimental studies, clinical trials with either human IL-4 or IL-10 in RA patients did not lead to substantial disease suppression. Based on a thorough evaluation of the actions of IL-4 and IL-10 in these studies, it is hypothesized that disease suppression of RA may require the concerted action of suppressive Th2 cytokines or Th2 activity.


Assuntos
Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Citocinas/metabolismo , Células Th2/metabolismo , Animais , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Citocinas/agonistas , Citocinas/imunologia , Humanos , Inflamação/imunologia , Inflamação/prevenção & controle , Interleucina-10/agonistas , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-4/agonistas , Interleucina-4/imunologia , Interleucina-4/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia
10.
J Immunol ; 161(3): 1074-7, 1998 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-9686563

RESUMO

Binding of IL-4 to its cognate receptor leads to the activation of a number of signaling pathways within the cell. Activation of the transcription factor STAT6 by JAK family protein tyrosine kinases has been shown to be essential for the full response of cells to IL-4. To elucidate the role of STAT6 in IL-4 signaling, we have constructed and expressed in cells a conditionally active form of the protein (STAT6:ER*) by fusing STAT6 to a modified form of the hormone-binding domain of the estrogen receptor. Activation of STAT6:ER* by 4-hydroxytamoxifen leads to specific activation of STAT6-regulated gene expression including the activation of a STAT6 reporter construct and induction of CD23 in B cell lines. Interestingly, in contrast to native STAT6, activation of STAT6:ER* occurs in the absence of detectable tyrosine phosphorylation of the fusion protein. This type of conditional system will be helpful in dissecting the mechanisms and specificity of transcriptional regulation by the STAT family of transcription factors.


Assuntos
Interleucina-4/agonistas , Interleucina-4/fisiologia , Transativadores/fisiologia , Animais , Linhagem Celular , Proteínas de Ligação a DNA/fisiologia , Vetores Genéticos/síntese química , Vetores Genéticos/imunologia , Humanos , Interferon gama/fisiologia , Camundongos , Fosforilação , Receptores de IgE/biossíntese , Proteínas Recombinantes de Fusão/metabolismo , Retroviridae/imunologia , Fator de Transcrição STAT1 , Fator de Transcrição STAT6 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Transativadores/biossíntese , Transativadores/genética , Ativação Transcricional/efeitos dos fármacos , Tirosina/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
11.
Proc Natl Acad Sci U S A ; 95(16): 9454-8, 1998 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-9689101

RESUMO

Interleukin 4 (IL-4) is a pleiotropic cytokine. Of the cell types responsive to IL-4, T cells express one IL-4 receptor (IL-4R) type, IL-4Ralpha/IL-2Rgamma (class I IL-4R), whereas endothelial cells express another type, IL-4Ralpha/IL-13Ralpha (class II IL-4R). It was hypothesized that IL-4 variants could be generated that would be selective for cell types expressing the different IL-4Rs. A series of IL-4 muteins were generated that were substituted in the region of IL-4 implicated in interactions with IL-2Rgamma. These muteins were evaluated in T cell and endothelial cell assays. One of these muteins, containing the mutation Arg-121 to Glu (IL-4/R121E), exhibited complete biological selectivity for T cells, B cells, and monocytes, but showed no activity on endothelial cells. Receptor binding studies indicated that IL-4/R121E retained physical interaction with IL-2Rgamma but not IL-13Ralpha; consistent with this observation, IL-4/R121E was an antagonist of IL-4-induced activity on endothelial cells. IL-4/R121E exhibits a spectrum of activities in vitro that suggest utility in the treatment of certain autoimmune diseases.


Assuntos
Interleucina-4/agonistas , Linfócitos B/imunologia , Linfócitos B/metabolismo , Ligação Competitiva , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Interleucina-4/metabolismo , Receptores de Interleucina-4/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
12.
Int Immunol ; 8(11): 1751-8, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8943570

RESUMO

Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by the severe T lymphopenia observed in IL-7-deficient mice. We recently reported that IL-7 preferentially promotes the in vitro expansion of a discrete MHC class I-dependent lymphocyte subset comprising both CD4+ and CD4-CD8- TCR alpha beta + cells bearing several NK cells markers such NK1.1 and Ly-49. These T cells, designated as NK1+ T cells, have the unique property among thymocytes of producing large amounts of IL-4 upon primary stimulation via the TCR. We have further demonstrated that thymic NK1+ T cells of non-obese diabetic (NOD) mice, a spontaneous model of autoimmune type I diabetes, are markedly deficient in maturation both quantitatively and functionally (IL-4 production). In the present experiments, the addition of exogenous IL-7 completely restored IL-4 production by anti-TCR alpha beta-stimulated mature (HSA-CD8-) thymocytes in NOD mice. A short 2 h preincubation with IL-7 was sufficient to restore both the expression of IL-4 mRNA and IL-4 production capacity. This was related to a direct effect on NK1+ thymocytes since: (i) the effect of IL-7 was restricted to the non-mainstream MEL-14- 3G11- TCR alpha beta + subset which mostly concentrates the IL-4-producing capacity and (ii) IL-7 did not restore IL-4 production in class I-deficient mice which lack the NK1+ T cell subset. Importantly, this activity of IL-7 on NK1+ T cells was also demonstrated in non-autoimmune strains of mice. These results were extended in vivo by showing that the IL-7 treatment significantly increased the anti-CD3 triggered IL-4 production by NK1+ T spleen cells. These findings confirm the role of IL-7 in NK1+ T cell maturation and suggest that the NK1+ T cell defect in NOD mice could be related to insufficient intrathymic IL-7 bioavailability.


Assuntos
Antígenos Ly , Antígenos/análise , Interleucina-4/agonistas , Interleucina-4/biossíntese , Interleucina-7/farmacologia , Glicoproteínas de Membrana/análise , Proteínas/análise , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Regulação para Cima/imunologia , Animais , Antígenos de Superfície/análise , Diferenciação Celular/efeitos dos fármacos , Feminino , Interleucina-4/genética , Lectinas Tipo C , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Subfamília B de Receptores Semelhantes a Lectina de Células NK , RNA Mensageiro/análise , Receptores Semelhantes a Lectina de Células NK , Proteínas Recombinantes/farmacologia , Subpopulações de Linfócitos T/imunologia
13.
Immunol Lett ; 51(3): 169-73, 1996 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8832287

RESUMO

The in vitro immunopharmacologic effect of suramin, a polysulfonated napthylurea, was examined on splenocytes and T helper (Th) 1 and 2 clones. Cytokine capture assays revealed that suramin inhibited the production of IFN-gamma, whilst IL-4 is increased in splenocytes. To examine whether suramin preferentially acts on Th cells, clones SP39A1 and SP41D5 were used. The former is a Th1 clone, whereas the latter is Th2. Suramin also inhibited IFN-gamma production by SP39A1, whilst IL-4 production by SP41D5 was enhanced. The action of suramin was of a dose-dependent nature. With regards to T cell proliferation, suramin inhibited the proliferation of both SP39A1 and SP41D5. The ability of suramin to manipulate Th subset cytokine balance can render it a feasible therapeutic agent in autoimmune disorders such as multiple sclerosis.


Assuntos
Citocinas/análise , Suramina/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Doenças Autoimunes/tratamento farmacológico , Células Cultivadas , Células Clonais , Feminino , Interferon gama/análise , Interferon gama/antagonistas & inibidores , Interleucina-4/agonistas , Interleucina-4/análise , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos , Baço/citologia , Baço/efeitos dos fármacos , Suramina/uso terapêutico , Linfócitos T Auxiliares-Indutores/classificação
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