Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients
Down-regulation of the anti-inflammatory protein annexin A1 in cystic fibrosis knock-out mice and patients
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DOI：
10.1074/mcp.m500019-mcp200
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发表时间：
2005-10-01
影响因子：
7
通讯作者：
Edelman, A
中科院分区：
文献类型：
--
作者：
Bensalem, N;Ventura, AP;Edelman, A
囊性纤维化是一种致命的人类遗传性疾病，由编码cAMP激活氯离子通道的CFTR基因突变引起。其特征在于通过分泌上皮的异常液体运输和肺、胰腺和肠中的慢性炎症。由于囊性纤维化（CF）的病理生理学不能仅仅用囊性纤维化跨膜传导调节因子（CFTR）的功能障碍来解释，我们应用蛋白质组学方法（双向电泳和质谱）来寻找缺乏CFTR的小鼠之间差异表达的蛋白质（cftr（tm 1Unc），cftr（-/-））和对照，使用来自年幼动物的结肠隐窝，即在肠道炎症发展之前。通过分析在pH 6 - 11范围内分离的总蛋白，我们检测到24个差异表达蛋白（> 2倍）。在这项工作中，我们专注于cftr（-/-）小鼠的二维凝胶中不存在的这些蛋白质之一。该蛋白质点（分子量，37 kDa; pI 7）通过质谱法鉴定为膜联蛋白A1，一种抗炎蛋白。有趣的是，膜联蛋白A1在cftr（-/-）小鼠的肺和胰腺中也检测不到，这些组织已知表达CFTR。宿主炎症反应抑制介质的缺失与结肠促炎细胞溶质磷脂酶A的上调有关（2）。更重要的是，膜联蛋白A1在CFTR基因（Y122 X，489 delC）携带纯合无义突变的CF患者的鼻上皮细胞中下调，并在F508 del患者中差异表达。这些结果表明，膜联蛋白A1可能是一个关键的蛋白质参与CF发病机制，特别是在有关不明确的领域炎症CF。我们认为，膜联蛋白A1的表达减少有助于CF表型的恶化。
Cystic fibrosis is a fatal human genetic disease caused by mutations in the CFTR gene encoding a cAMP-activated chloride channel. It is characterized by abnormal fluid transport across secretory epithelia and chronic inflammation in lung, pancreas, and intestine. Because cystic fibrosis (CF) pathophysiology cannot be explained solely by dysfunction of cystic fibrosis transmembrane conductance regulator ( CFTR), we applied a proteomic approach ( bidimensional electrophoresis and mass spectrometry) to search for differentially expressed proteins between mice lacking cftr (cftr(tm1Unc), cftr(-/-)) and controls using colonic crypts from young animals, i.e. prior to the development of intestinal inflammation. By analyzing total proteins separated in the range of pH 6 - 11, we detected 24 differentially expressed proteins (> 2-fold). In this work, we focused on one of these proteins that was absent in two-dimensional gels from cftr(-/-) mice. This protein spot ( molecular mass, 37 kDa; pI 7) was identified by mass spectrometry as annexin A1, an anti-inflammatory protein. Interestingly, annexin A1 was also undetectable in lungs and pancreas of cftr(-/-) mice, tissues known to express CFTR. Absence of this inhibitory mediator of the host inflammatory response was associated with colonic up-regulation of the proinflammatory cytosolic phospholipase A(2). More importantly, annexin A1 was down-regulated in nasal epithelial cells from CF patients bearing homozygous nonsense mutations in the CFTR gene (Y122X, 489delC) and differentially expressed in F508del patients. These results suggest that annexin A1 may be a key protein involved in CF pathogenesis especially in relation to the not well defined field of inflammation in CF. We suggest that decreased expression of annexin A1 contributes to the worsening of the CF phenotype.