RESUMO
CD8 lymphocytes play a role in aortic valve inflammation leading to aortic valve calcification (AVC). RANK is a transmembrane protein that is important in osteoclast differentiation and calcification. Beta-glucosylceramide (beta-GC) together with beta-lactosylceramide (beta-LC), the 1:1 combination of beta- glucosylceramide and beta-lactosylceramide, designated IGL, exerts an immune modulatory effect in various inflammatory disorders in a CD8- and NKT (natural killer T cell)-dependent manner. We hypothesized that IGL may affect the inflammatory condition associated with AVC. AVC was induced in rats by oral administration of a high-adenine, high-phosphorus diet and was assessed by multislice computer tomography. Administration of this diet was associated with a marked increase in CD8 and NKT lymphocyte accumulation in the aortic valve. Administration of IGL led to marked suppression of RANK expression, associated with inhibition of both NKT and CD8 lymphocyte accumulation in the aortic valve. These effects were associated with a significant improvement in the degree of AVC in IGL-treated animals (25 and 53 by Agatston Score, in IGL-treated and controls, respectively). CD8 and NKT lymphocytes play a role in the pathogenesis of AVC, and RANK-mediated NKT inhibition by beta-glycosphingolipids can alleviate AVC.
Assuntos
Valva Aórtica/imunologia , Linfócitos T CD8-Positivos/imunologia , Calcinose/imunologia , Glicoesfingolipídeos/metabolismo , Doenças das Valvas Cardíacas/imunologia , Células T Matadoras Naturais/imunologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/metabolismo , Valva Aórtica/patologia , Apoptose , Linfócitos T CD8-Positivos/metabolismo , Calcinose/diagnóstico por imagem , Calcinose/metabolismo , Calcinose/prevenção & controle , Modelos Animais de Doenças , Regulação para Baixo , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/prevenção & controle , Hiperfosfatemia/imunologia , Masculino , Células T Matadoras Naturais/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal/imunologia , Índice de Gravidade de Doença , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: beta-Glucosylceramide, a naturally occurring glycolipid, exerts modulatory effects on natural killer T (NKT) lymphocytes. AIM: To determine whether beta-glucosylceramide can alter NKT function in opposite directions, colitis was induced by intracolonic installation of trinitrobenzenesulphonic acid, and hepatocellular carcinoma (HCC) was induced by transplantation of Hep3B cells. METHODS: The immunological effect of beta-glucosylceramide was assessed by analysis of intrahepatic and intrasplenic lymphocyte populations, serum cytokines and STAT protein expression. RESULTS: Administration of beta-glucosylceramide led to alleviation of colitis and to suppression of HCC, manifested by improved survival and decreased tumour volume. The beneficial effects were associated with an opposite immunological effect in the two models: the peripheral:intrahepatic CD4:CD8 lymphocyte ratio increased in the colitis model and decreased in the HCC group. The peripheral:intrahepatic NKT lymphocyte ratio decreased in beta-glucosylceramide-treated mice solely in the HCC model. The effect of beta-glucosylceramide was associated with decreased STAT1 and 4 expression, and with overexpression of STAT6, along with decreased interferon gamma levels in the colitis model, whereas an opposite effect was noted in the HCC model. CONCLUSIONS: beta-glucosylceramide alleviates immunologically incongruous disorders and may be associated with "fine tuning" of immune responses, by changes in plasticity of NKT lymphocytes.
