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，锡钙素-1(STC1)减少 巨噬细胞对趋化物质的反应和跨越内皮单分子层的迁移。STc1也 通过诱导解偶联蛋白-2(UCP2)减少巨噬细胞中超氧化物的产生，并抑制 核因子-B途径。在培养的内皮细胞中，STC1抑制细胞因子诱导的通透性和紧张性变化 连接蛋白的表达。STC1转基因小鼠，表现出较高的血清水平和优先 STC1在巨噬细胞和内皮细胞中的表达，显示肾小球中炎症较轻的巨噬细胞 在抗肾小球基底膜(GBM)疾病期间，导致肾脏保护。总括 假设：STC1通过抑制巨噬细胞募集和功能来抑制炎症，并且 细胞因子诱导的内皮通透性增加。在具体目标一中，我们将确定 STc1上调UCP2表达及超氧化物在STc1抑制巨噬细胞核因子-βB中的作用 在特定的目标II中，我们将确定STC1在细胞因子诱导的表达变化和 在原代培养的肾内皮细胞中组装紧密连接蛋白。在具体目标三中，在 在抗GBM疾病的背景下，我们将检测自体肾血管的内皮通透性，以及 肾内皮细胞特异性或巨噬细胞特异性过度表达后的肾脏炎症和功能 或STc1的删除。

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.