Stanniocalcin-1, a novel anti-inflammatory protein

巨噬细胞是炎症的重要介质。我们的数据显示斯钙素-1（STC 1）降低 巨噬细胞对化学引诱物的反应和穿过内皮单层的迁移。STC 1也 通过诱导解偶联蛋白-2（UCP 2）减少巨噬细胞中超氧化物的产生，并抑制 NF-B通路。在培养的内皮细胞中，STC 1抑制了精氨酸诱导的通透性和紧密性的变化。 连接蛋白表达。STC 1转基因小鼠，其表现出升高的血清水平和优先的 STC 1在巨噬细胞和内皮细胞中的表达，显示肾小球中的炎性巨噬细胞较少 在抗肾小球基底膜（GBM）疾病，导致肾脏保护。整体 假设：STC 1通过抑制巨噬细胞募集和功能来抑制炎症， 苦参碱诱导的内皮通透性增加。在具体目标I中，我们将确定 STC 1上调UCP 2和超氧化物在STC 1介导的巨噬细胞NF-B抑制中的作用 在特定目标II中，我们将确定STC 1对精氨酸诱导的表达变化的影响， 在培养的原代肾内皮细胞中紧密连接蛋白的组装。在具体目标三中， 在抗GBM疾病的背景下，我们将检查天然肾血管的内皮通透性，以及 肾内皮特异性或巨噬细胞特异性过表达后的肾脏炎症和功能 或缺失STC 1。

Macrophages are important mediators of inflammation. Our data show stanniocalcin-1 (STC1) decreases macrophage response to chemoattractants and migration across an endothelial monolayer. STC1 also diminishes superoxide generation in macrophages, by inducing uncoupling protein-2 (UCP2), and inhibits the NF-¿B pathway. In cultured endothelial cells, STC1 inhibits cytokine-induced changes in permeability and tight junction protein expression. STC1 transgenic mice, which exhibit elevated serum levels and preferential expression of STC1 in macrophages and endothelium, display less inflammatory macrophages in the glomeruli during anti-glomerular basement membrane (GBM) disease, resulting in kidney protection. Overall hypothesis: STC1 suppresses inflammation through inhibition of macrophage recruitment and function, and cytokine-induced increase in endothelial permeability. In Specific Aim I, we will determine mechanisms of UCP2 upregulation by STC1 and the role of superoxide in STC1-mediated inhibition of NF-¿B in macrophages. In Specific Aim II, we will determine the effect of STC1 on cytokine-induced changes in expression and assembly of tight junction proteins in cultured primary kidney endothelial cells. In Specific Aim III, in the context of anti-GBM disease, we will examine endothelial permeability of native kidney vessels, as well as kidney inflammation and function, after kidney endothelium-specific or macrophage-specific overexpression or deletion of STC1.