RESUMEN
SAP is an adaptor protein that is expressed in NK and T cells. It is mutated in humans who have X-linked lymphoproliferative (XLP) disease. By interacting with SLAM family receptors, SAP enables tyrosine phosphorylation signaling of these receptors by its ability to recruit the Src-related kinase, Fyn. Here, we analyzed the role of SAP in NK cell functions using the SAP-deficient mouse model. Our results showed that SAP was required for the ability of NK cells to eliminate tumor cells in vitro and in vivo. This effect strongly correlated with expression of CD48 on tumor cells, the ligand of 2B4, a SLAM-related receptor expressed in NK cells. In keeping with earlier reports that studied human NK cells, we showed that SAP was necessary for the ability of 2B4 to trigger cytotoxicity and IFN-gamma secretion. In the absence of SAP, 2B4 function was shifted toward inhibition of NK cell-mediated cytotoxicity. By analyzing mice lacking Fyn, we showed that similarly to SAP, Fyn was strictly required for 2B4 function. Taken together, these results provide evidence that the 2B4-SAP-Fyn cascade defines a potent activating pathway of natural cytotoxicity. They also could help to explain the high propensity of patients who have XLP disease to develop lymphoproliferative disorders.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Citotoxicidad Inmunológica , Proteínas Proto-Oncogénicas/metabolismo , Familia-src Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Secuencia de Bases , Antígeno CD48 , ADN Complementario/genética , Humanos , Técnicas In Vitro , Interferón gamma/biosíntesis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-fyn , Tirosina/metabolismo , Familia-src Quinasas/deficiencia , Familia-src Quinasas/genéticaRESUMEN
<p><b>OBJECTIVE</b>To study the effect of sour TCM compound Recipe (SCCR) on insulin resistance in experimental rats with diabetes mellitus type 2 (DM2), under the guidance of TCM doctrine of "sour restrains sweet".</p><p><b>METHODS</b>Model rats of DM2 were established by 8 weeks' feeding with high calorie forage combined with intraperitoneal injection of small dose of streptozotocin, and treated with SCCR (15 g/kg of crude drug/day). Levels of fasting blood glucose (FBG), serum insulin, free fatty acids (FFA), tumor necrosis factor a (TNF-alpha), combining capacity and constant of insulin receptor in liver were determined before treatment and 4, 8 and 12 weeks after treatment, and the insulin sensitive index was calculated. The data were compared with those in the model group (untreated), sweet TCM compound recipe group and bitter TCM compound group (treated with sweet and bitter Chinese drugs respectively) and the control group (treated with dimethyldiguanide).</p><p><b>RESULTS</b>SCCR could markedly reduce the FBG, serum FFA and TNF-alpha levels in rat model of DM2, stimulate the secretion of insulin, raise the combining capacity and constant of insulin receptor in liver and improve the insulin sensitivity, as compared with the effect of sweet or bitter Chinese compound recipe, the difference was significant (P < 0.05).</p><p><b>CONCLUSION</b>SCCR could improve the glucose metabolic disorder and ameliorate the degree of insulin resistance in DM2 model rats, with the effect superior to those with sweet or bitter taste, which illustrates primarily that the therapeutic principle of "sour restrains sweet" of TCM is true of science in a certain degree and having its guiding significance in clinical practice.</p>