SHP-2酪氨酸磷酸酶激活突变促进组织白细胞浸润和器官损伤  

Gain-of-Function Mutations in SHP-2 Tyrosine Phosphatase(SHP-2^(D61G/+)) Induce Leukocyte Infiltration and Multi-Organ Impairment

作　　者：胡中倩[1] 汪心怡[1] 储著朗[1] 郑贤芳[1] 陈吉[1] 余科科[1] 李菲菲[1] 瞿成奎[2] 汪思应[1] 

机构地区：[1]安徽医科大学病理生理学教研室,合肥230032 [2]美国凯斯西储大学,克里夫兰44106

出　　处：《中国比较医学杂志》2011年第12期10-13,93,共5页Chinese Journal of Comparative Medicine

基　　金：国家自然科学基金(编号:30873046;309734246);安徽省留学回国人员科研项目(编号:2009-2011);安徽省学科学术带头人基金

摘　　要：目的观察SHP-2D61G/+酪氨酸磷酸酶激活突变对组织白细胞浸润、细胞因子分泌及多器官损伤的影响。方法分别以SHP-2D61G/+激活突变敲入的模型小鼠和野生型C57BL/6小鼠为研究对象,ELISA法检测小鼠血清和白细胞培养上清液中IL-2及TNF-α浓度;采用常规组织切片和HE染色观察心、肺、脾等组织病理学改变;放射免疫法检测血清中丙氨酸转氨酶和心肌肌钙蛋白I的水平。结果 SHP-2D61G/+激活突变小鼠脾、肺组织中白细胞浸润较野生型对照小鼠明显增加,心肌肥大,出现明显炎症损伤型组织学变化;与野生型对照相比,突变小鼠血清及白细胞培养上清液中IL-2和TNF-α浓度均显著增加(P<0.01),血清丙氨酸转氨酶及心肌肌钙蛋白I水平亦显著增高(P<0.01)。结论 SHP-2D61G/+激活突变增强白细胞分泌炎症因子的能力,促进组织白细胞严重浸润和脾、肺、心等多器官损伤,进而导致多器官功能障碍。Objective To investigate the effects of SHP-2^D61G/＋ mutations on leukocyte infiltration, cytokines secretion and multi-organ impairment. Methods The SHP-2^D61G/＋ gain-of-function mutant gene knock-in model mice and wild-type 57BL/6 mice （WT） were used in this study. Serum level of IL-2 and TNF-α and the cytokines concentration in the supernatant of cultured WBC were quantified by enzyme-linked immunosorbent assay （ ELISA）. Leukocyte infiltration in the lung, spleen and heart tissues was observed by histopathology, and serum levels of alanine aminotransferase （ALT） and cardiac troponin I （cTnI） were studied by radioimmunoassay. Results Compared with the WT control, leukocyte infiltration in the lung and spleen tissues were significantly increased and myocardial hypertrophy was observed in theSHP-2^D61G/＋ mutant mice. The serum levels of IL-2 and TNF-α were significantly increased in SHP-2^D61G/＋ mutant mice （P 〈 0. 01, compared with the WT control） , and so were the cytokines concentrations in the supernatant of cultured WBC （P 〈0.01, compared with the WT control）. The serum levels of ALT and cTnl were significantly higher in the SHP-2^D61G/＋ mutant mice than that of the WT controls （P 〈 O. 01 ）. Conclusions Gain-of-function mutations in SHP-2 tyrosine phosphatase （SHP-2^D61G/＋） greatly induce leukocyte infiltration in tissues, IL-2 and TNF-α secretion and multi-organ impairment, which may lead to multiple organ failure.

关 键 词：SHP-2酪氨酸磷酸酶 激活突变 细胞因子分泌 白细胞浸润 多器官损伤 

分 类 号：R33[医药卫生—人体生理学]