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J Leukoc Biol ; 75(6): 1139-46, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15020655

RESUMO

We previously reported that disaccharides (DS), generated by enzymatic degradation of heparin or heparan sulfate, inhibit T cell-mediated immune reactions in rodents and regulate cytokine [tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-8, and IL-1beta] secretion by T cells, macrophages, or intestinal epithelial cells. Here, we investigated the effects of a trisulfated heparin DS (3S-DS) on two aspects of T cell function: secretion of proinflammatory cytokines and migration to an inflamed site. 3S-DS down-regulated nuclear factor-kappaB activity and reduced the secretion of TNF-alpha and interferon-gamma (IFN-gamma) by anti-CD3-activated T cells. In addition, 3S-DS inhibited CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor-1alpha)-dependent migration in vitro and in vivo and decreased CXCL12-induced T cell adhesion to the extracellular matrix glycoprotein, fibronectin (FN). This inhibition was accompanied by attenuation of CXCL12-induced Pyk2 phosphorylation but did not involve internalization of the CXCL12 receptor, CXCR4, or phosphorylation of extracellular-regulated kinase. Despite inhibiting CXCL12-induced adhesion, 3S-DS, on its own, induced T cell adhesion to FN, which was accompanied by phosphorylation of Pyk2. A monosulfated DS showed no effect. Taken together, these data provide evidence that 3S-DS can regulate inflammation by inducing and modulating T cell-signaling events, desensitizing CXCR4, and modulating T cell receptor-induced responses.


Assuntos
Movimento Celular/efeitos dos fármacos , Dissacarídeos/farmacologia , Heparina/análogos & derivados , Heparina/farmacologia , NF-kappa B/metabolismo , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Animais , Anticorpos Monoclonais/farmacologia , Medula Óssea/metabolismo , Adesão Celular/efeitos dos fármacos , Quimiocina CXCL12 , Quimiocinas CXC/metabolismo , Quimiotaxia , Fibronectinas/metabolismo , Quinase 2 de Adesão Focal , Heparitina Sulfato/farmacologia , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CXCR4/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
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