RESUMO
The transcription factor Fli-1 is implicated in the pathogenesis of both murine and human lupus. Increased levels of Fli-1 mRNA were present in the peripheral blood lymphocytes from lupus patients; furthermore, transgenic overexpression of Fli-1 in normal mice resulted in the development of a lupus-like disease. Lupus nephritis is a major cause of death in both lupus patients as well as in animal models. In this study, we generated Fli-1 heterozygous knockout (Fli-1(+/)â» ) NZM2410 mice (of which the wild-type is a widely used lupus murine model) that expressed decreased levels of Fli-1 and investigated the impact of Fli-1 expression on lupus nephritis development and survival. Ninety-three per cent of the Fli-1(+/)â» NZM2410 mice survived to the age of 52 weeks compared to only 35% of wild-type NZM2410 mice. Autoantibodies, including anti-dsDNA and anti-glomerular basement antigen, in Fli-1(+/)â» NZM2410 mice were statistically significantly lower when compared to wild-type NZM2410 mice at the ages of 30 and 34 weeks. Total B cell and activated B cell populations in the spleens from Fli-1(+/)â» NZM2410 mice were decreased significantly compared to wild-type NZM2410 mice. Fli-1(+/)â» NZM2410 mice also had remarkably diminished proteinuria and decreased renal pathological scores when compared with wild-type NZM2410 mice. Expression of early growth response 1 (Egr-1) was decreased significantly in the kidneys from Fli-1(+/)â» NZM2410 mice when compared to wild-type littermates. Our data indicate that expression of Fli-1 plays an important role in lupus disease development in NZM2410 mice.
Assuntos
Formação de Anticorpos/genética , Autoanticorpos/sangue , Nefrite Lúpica/imunologia , Proteína Proto-Oncogênica c-fli-1/genética , Animais , Anticorpos Antinucleares/sangue , Formação de Anticorpos/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Contagem de Células , Proteína 1 de Resposta de Crescimento Precoce/genética , Feminino , Expressão Gênica/genética , Imunoglobulina G/sangue , Rim/metabolismo , Rim/patologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Nefrite Lúpica/urina , Masculino , Camundongos , Camundongos Endogâmicos MRL lpr , Camundongos Knockout , Proteinúria/urina , Baço/citologia , Baço/imunologia , Análise de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologiaRESUMO
The transcription factor Fli-1 is implicated in the pathogenesis of both murine and human lupus. Decreased expression of Fli-1 in heterozygous (Fli-1(+/-)) Murphy Roths Large (MRL)/lpr mice resulted in significantly lower kidney pathological scores and markedly increased survival. In this study, bone marrow (BM) transplantation was used to investigate the role of decreased expression of Fli-1 in haematopoietic versus non-haematopoietic cell lineages in autoimmune disease development. Wild-type (WT) MRL/lpr that received BM from Fli-1(+/-) MRL/lpr mice had statistically significantly lower autoantibodies, less proteinuria, reduced renal disease and prolonged survival compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. Although not statistically significant, Fli-1(+/-) MRL/lpr mice that received BM from WT MRL/lpr mice also had lower autoantibodies and improved survival compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. Our data indicate that expression of Fli-1 in haematopoietic cell lineages has a significant effect on disease development in MRL/lpr mice.