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1.
Vet Pathol ; 48(4): 885-95, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21149847

RESUMO

Glucocorticoids (GCs), despite having many undesirable side effects, remain effective for the treatment of many inflammatory diseases and are commonly used as benchmark drugs in animal models of disease. However, the molecular mechanisms underling systemic GC effects in these models are poorly characterized. In this study, prednisolone and dexamethasone were evaluated in the fully established Lewis rat adjuvant-induced arthritis (AIA) model. In AIA, adjuvant administration induced polyarticular and systemic inflammation, which included spleen and liver. In the liver, multifocal hepatic granulomas were observed. To characterize the systemic response and the pathways responsible for GC effects, histology, transcriptional profiling, and immunohistochemistry (IHC) were performed. There was a decrease in the incidence and histologic severity score for granulomas with GC treatment. There was no effect on cellular composition of granulomas as assessed by IHC for CD3+ lymphocytes, macrophages, and B cells, but there was a significant reduction in infiltrating lymphocytes in the hepatic parenchyma. By Affymetrix microarray analysis, 10% of hepatic transcripts were altered (P<.01) in livers from AIA rats, with ~31% of them partially reversed with treatment with dexamethasone and ~13% with prednisolone. Many of these altered hepatic transcripts correspond to human genes that are dysregulated in the synovium in human rheumatoid arthritis (RA), indicating that the rat AIA model shares features with human RA. These data establish molecular changes in the liver and the effect of GCs in rat AIA, which can be used to aid in understanding the mechanism of action of novel anti-inflammatory compounds in this animal model.


Assuntos
Artrite Experimental/tratamento farmacológico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Fígado/metabolismo , Prednisolona/uso terapêutico , Transcrição Gênica/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Dexametasona/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Perfilação da Expressão Gênica , Glucocorticoides/administração & dosagem , Masculino , Prednisolona/administração & dosagem , Ratos , Ratos Endogâmicos Lew
2.
J Immunol ; 161(10): 5614-20, 1998 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-9820540

RESUMO

The recently described IL-1R accessory protein (IL-1R AcP) interacts with IL-1beta and the IL-1 type-IR (IL-1RI), but an essential requirement for IL-1R AcP in IL-1 signaling in vitro has not been established and its role in vivo has not been examined. In this study, IL-1R AcP-deficient mice and fibroblasts were produced and characterized. All IL-1 agonists bound to IL-1R AcP-deficient cells through the type I IL-1R, but failed to activate gene expression through either the nuclear factor-kappaB or AP-1-dependent signaling pathways. Absence of IL-1R AcP differentially affected the affinity for IL-1 ligands. IL-1R AcP-deficient fibroblasts bound murine IL-1alpha and human IL-1R antagonist protein (IL-1Ra) with only moderately reduced affinity when compared with wild-type cells, whereas murine IL-1beta affinity was reduced by 70-fold. IL-1 also failed to produce a biologic response in vivo in IL-1R AcP-deficient mice. These data demonstrate that a type I IL-1R/IL-1R AcP complex is required for signaling by all IL-1 agonists and for high affinity binding by IL-1beta. Finally, IL-1R AcP is an essential signal transducing component of the functional IL-1R and should represent a novel target for blocking IL-1 function in human disease.


Assuntos
Proteínas/fisiologia , Receptores de Interleucina-1/fisiologia , Animais , Ligação Competitiva/imunologia , Linhagem Celular , Embrião de Mamíferos , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica/imunologia , Marcação de Genes , Interleucina-1/farmacologia , Proteína Acessória do Receptor de Interleucina-1 , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Proteínas/genética , Receptores de Interleucina-1/genética , Células-Tronco , Fator de Necrose Tumoral alfa/farmacologia
3.
Eur J Immunol ; 26(12): 2933-8, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8977288

RESUMO

Collagen-induced arthritis (CIA) is an animal model for rheumatoid arthritis. The disease is elicited by immunization of genetically susceptible DBA/1 mice with type II collagen, resulting in a debilitating arthritis characterized by inflammation and involvement of multiple joints. We investigated the role of endogenous interleukin (IL)-12 in the pathogenesis of this disease by undertaking an analysis of IL-12-deficient mice on the DBA/1 genetic background after immunization with type II collagen. Both the incidence and severity of disease were significantly reduced in mice unable to produce biologically active IL-12. Concomitant decreases were observed in serum levels of pathogenic, collagen-specific IgG2a antibodies and collagen-induced secretion of interferon-gamma by immune splenocytes in vitro, consistent with an impaired T helper-1 response. There were, however, a few animals which developed severe disease in a single paw in spite of this highly diminished Th1 response. Taken together, these results demonstrate an important role for IL-12 in the pathogenesis of CIA, although it is not absolutely required for disease development.


Assuntos
Artrite Experimental/epidemiologia , Artrite Experimental/patologia , Colágeno/toxicidade , Interleucina-12/deficiência , Interleucina-12/toxicidade , Animais , Artrite Experimental/induzido quimicamente , Colágeno/imunologia , Imunoglobulina G/imunologia , Incidência , Interleucina-12/genética , Camundongos , Camundongos Endogâmicos DBA , Camundongos Mutantes
4.
Ciba Found Symp ; 189: 17-28; discussion 28-34, 77-8, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-7587631

RESUMO

A variety of adhesion molecules have been identified which mediate the interaction of leukocytes with endothelial cells. In order to define the role of individual molecules in inflammation we have produced lines of mice which are deficient in the synthesis of specific adhesion molecules. Null mutations were introduced into the genes encoding E-selectin or vascular cell adhesion molecule-1 (VCAM-1) in embryonic stem cells and these cells were used to produce lines of mice carrying the mutation. E-selectin-deficient mice were viable and exhibited no developmental defects. The roles of E- and P-selectin in the influx of neutrophils were examined using these mice. The data suggest that the two selectins are functionally redundant in mediating neutrophil emigration in a model of chemically induced peritonitis. VCAM-1-deficient mice are not viable. Analysis of VCAM-1 gene expression in wild-type embryos and phenotypic analysis of VCAM-1 -/- embryos suggests that VCAM-1 is required for development of the extraembryonic circulatory system and the embryonic heart.


Assuntos
Selectina E/fisiologia , Camundongos Mutantes , Molécula 1 de Adesão de Célula Vascular/fisiologia , Animais , Adesão Celular , Desenvolvimento Embrionário e Fetal , Camundongos , Neutrófilos/fisiologia
5.
Immunity ; 1(8): 709-20, 1994 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7541306

RESUMO

The initial rolling interaction of leukocytes with the blood vessel wall during leukocyte trafficking has been postulated to rely on members of the selectin family of adhesion molecules. Two selectins, E-selectin and P-selectin, have been identified that are expressed on activated endothelial cells. Mice deficient in E-selectin expression have been produced in order to examine the role of this selectin in leukocyte trafficking. Mice homozygous for an E-selectin null mutation were viable and exhibited no obvious developmental alterations. E-selectin-deficient mice displayed no significant change in the trafficking of neutrophils in several models of inflammation. However, blocking both endothelial selectins by treatment of the E-selectin-deficient animals with an anti-murine P-selectin antibody, 5H1, significantly inhibited neutrophil emigration in two distinct models of inflammation. While neutrophil accumulation at early times during thioglycollate-induced peritonitis was dependent on P-selectin, neutrophil accumulation at later time points was blocked by 5H1 only in E-selectin-deficient mice but not in wild-type mice. Similarly, edema as well as leukocyte accumulation in a model of delayed-type hypersensitivity in the skin was almost completely prevented by blockade of P-selectin function with 5H1 in the E-selectin-deficient mice while the same treatment had no effect in wild-type mice. These data demonstrate that the majority of neutrophil migration in both models requires an endothelial selectin but that E-selectin and P-selectin are functionally redundant. These data have important implications in the use of selectin antagonists in the treatment of inflammatory disease.


Assuntos
Moléculas de Adesão Celular/fisiologia , Quimiotaxia de Leucócito , Inflamação/etiologia , Glicoproteínas da Membrana de Plaquetas/fisiologia , Animais , Anticorpos Monoclonais/farmacologia , Sequência de Bases , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/imunologia , Selectina E , Feminino , Rim/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Genéticos , Dados de Sequência Molecular , Mutagênese Insercional , Miocárdio/metabolismo , Neutrófilos/citologia , Selectina-P , Peritônio/citologia , Glicoproteínas da Membrana de Plaquetas/biossíntese , Glicoproteínas da Membrana de Plaquetas/imunologia , Fatores de Tempo , Molécula 1 de Adesão de Célula Vascular
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