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1.
J Exp Med ; 198(6): 937-45, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12975458

RESUMO

The cellular source of B cell activation factor (BAFF) required for peripheral B cell survival/maturation is unknown. To determine the nature of BAFF-producing cells we established and analyzed reciprocal bone marrow (BM) chimeras with wild-type (WT) and BAFF-deficient mice. The results revealed that BAFF production by radiation-resistant stromal cells is completely sufficient to provide a necessary signal for B cell survival/maturation, as BAFF-/- BM cells transferred into lethally irradiated WT mice gave rise to normal numbers of follicular (FO) and marginal zone (MZ) B cell subpopulations. On the other hand, transfer of WT BM into BAFF-/- lethally irradiated mice resulted only in minimal reconstitution of mature FO B cells and no restoration of MZ B cells. Thus, in the absence of BAFF+/+ stromal cells, BAFF production by BM-derived cells, presumably by macrophages, dendritic cells, and/or neutrophils, was not at all sufficient to support normal B cell homeostasis. Interestingly, immunization of both types of chimeras stimulated high levels of antigen-specific antibody secretion, indicating that either stromal cell- or hematopoietic cell-derived BAFF is sufficient for B cell antibody responses.


Assuntos
Linfócitos B/metabolismo , Homeostase , Proteínas de Membrana/metabolismo , Células Estromais/efeitos da radiação , Fator de Necrose Tumoral alfa/metabolismo , Animais , Fator Ativador de Células B , Células da Medula Óssea/metabolismo , Separação Celular , Sobrevivência Celular , Citometria de Fluxo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Radiação , Quimera por Radiação , Baço/citologia , Baço/metabolismo , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/genética
2.
J Leukoc Biol ; 82(1): 124-32, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17412915

RESUMO

Excessive scarring or fibrosis is a common feature of a wide spectrum of diseases characterized by an exaggerated Th2 response. The TLR/IL-1 receptor (IL-1R)-related protein ST2 is expressed in a membrane-bound form selectively by Th2 cells and was shown to be indispensable for some in vivo Th2 responses. ST2 was also found to block TLR signaling. We addressed the impact of the ST2 pathway on fibrogenesis using a mouse model of hepatic injury and fibrosis induced by carbon tetrachloride (CCl(4)). We showed that cytokine production by intrahepatic lymphocytes from CCl(4)-injured liver is abrogated in the absence of TLR-4. Interfering with the ST2 pathway using an ST2-Fc fusion protein accelerated and enhanced hepatic fibrosis, paralleled by the increasing ex vivo secretion of Th2 cytokines IL-4, -5, -10, and -13 by intrahepatic lymphocytes of ST2-Fc-treated, CCl(4)-gavaged mice. Absence of IL-4/13 signaling in IL-4Ralpha-deficient mice obliterated this ST2-Fc effect on fibrogenesis. Moreover, depletion of CD4(+) T cells abrogated ST2-Fc-enhanced Th2 cytokines and accelerated fibrosis. Thus, ST2-Fc caused overproduction of Th2 cytokines by intrahepatic CD4(+) T cells, possibly by modifying TLR-4 signaling in injured liver. This ST2-Fc-driven Th2 response exacerbated CCl(4)-induced hepatic fibrosis.


Assuntos
Citocinas/biossíntese , Fibrose/etiologia , Hepatopatias/imunologia , Proteínas de Membrana/farmacologia , Células Th2/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Tetracloreto de Carbono , Fibrose/induzido quimicamente , Fibrose/imunologia , Fragmentos Fc das Imunoglobulinas , Proteína 1 Semelhante a Receptor de Interleucina-1 , Hepatopatias/prevenção & controle , Camundongos , Receptores de Interleucina , Proteínas Recombinantes de Fusão
3.
J Biol Chem ; 278(35): 33127-33, 2003 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-12796483

RESUMO

BAFF is considered a therapeutic target because dysregulated production of BAFF can induce systemic lupus erythematosus-like phenotype in mice, and elevated levels of BAFF are associated with disease severity in systemic lupus erythematosus and rheumatoid arthritis patients. Fc fusion decoy receptors, BCMA-Fc and BAFF-R-Fc, are therapeutic candidates for blocking BAFF. While studying their interactions with BAFF, we found that BAFF-R-Fc is more effective than BCMA-Fc for blocking BAFF binding to its receptors. We also found that a trimeric BAFF can bind more than one BAFF-R-Fc but only one BCMA-Fc. Moreover, we show that, in contrast to monovalent BAFF-R-Fc, monovalent BCMA does not form stable complexes with BAFF. Differences in their interaction with BAFF predict BAFF-R-Fc would be a better inhibitor. Indeed, we show BAFF-R-Fc is 10-fold more efficacious than BCMA-Fc for blocking BAFF-induced B cell proliferation in vitro and for blocking BAFF-mediated survival of mouse splenic B lymphocytes in vivo.


Assuntos
Imunoglobulina G/química , Proteínas de Membrana/química , Receptores do Fator de Necrose Tumoral/química , Proteínas Recombinantes de Fusão/metabolismo , Fator de Necrose Tumoral alfa/química , Animais , Artrite Reumatoide/metabolismo , Asparagina/química , Fator Ativador de Células B , Receptor do Fator Ativador de Células B , Antígeno de Maturação de Linfócitos B , Linfócitos B/metabolismo , Células CHO , Membrana Celular/metabolismo , Separação Celular , Sobrevivência Celular , Cricetinae , Dimerização , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Leucina/química , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Prolina/química , Ligação Proteica , Baço/citologia , Valina/química
4.
Proc Natl Acad Sci U S A ; 99(2): 1035-40, 2002 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-11805342

RESUMO

The Kv4 A-type potassium currents contribute to controlling the frequency of slow repetitive firing and back-propagation of action potentials in neurons and shape the action potential in heart. Kv4 currents exhibit rapid activation and inactivation and are specifically modulated by K-channel interacting proteins (KChIPs). Here we report the discovery and functional characterization of a modular K-channel inactivation suppressor (KIS) domain located in the first 34 aa of an additional KChIP (KChIP4a). Coexpression of KChIP4a with Kv4 alpha-subunits abolishes fast inactivation of the Kv4 currents in various cell types, including cerebellar granule neurons. Kinetic analysis shows that the KIS domain delays Kv4.3 opening, but once the channel is open, it disrupts rapid inactivation and slows Kv4.3 closing. Accordingly, KChIP4a increases the open probability of single Kv4.3 channels. The net effects of KChIP4a and KChIP1-3 on Kv4 gating are quite different. When both KChIP4a and KChIP1 are present, the Kv4.3 current shows mixed inactivation profiles dependent on KChIP4a/KChIP1 ratios. The KIS domain effectively converts the A-type Kv4 current to a slowly inactivating delayed rectifier-type potassium current. This conversion is opposite to that mediated by the Kv1-specific "ball" domain of the Kv beta 1 subunit. Together, these results demonstrate that specific auxiliary subunits with distinct functions actively modulate gating of potassium channels that govern membrane excitability.


Assuntos
Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/química , Sequência de Aminoácidos , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Feminino , Técnicas In Vitro , Ativação do Canal Iônico , Cinética , Proteínas Interatuantes com Canais de Kv , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Oócitos/metabolismo , Canais de Potássio/genética , Canais de Potássio/metabolismo , Estrutura Terciária de Proteína , Subunidades Proteicas , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Homologia de Sequência de Aminoácidos , Canais de Potássio Shal , Xenopus
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