HDL/Apolipoprotein A-I Binds to Macrophage-Derived Progranulin and Suppresses its Conversion into Proinflammatory Granulins
HDL/Apolipoprotein A-I Binds to Macrophage-Derived Progranulin and Suppresses its Conversion into Proinflammatory Granulins
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DOI：
10.5551/jat.3921
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发表时间：
2010-01-01
影响因子：
4.4
通讯作者：
Matsuyama, Akifumi
中科院分区：
文献类型：
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作者：
Okura, Hanayuki;Yamashita, Shizuya;Matsuyama, Akifumi
目的：HDL对巨噬细胞具有抗炎作用，但其作用机制尚不清楚。我们假设HDL通过结合抑制巨噬细胞分泌因子向促炎因子的转化，并试图确定可能与HDL和/或载脂蛋白（apo） a - i形成复合物的因子。方法和结果：在从人单核细胞来源的巨噬细胞中获得的条件培养基中，我们发现了载脂蛋白A-I结合蛋白，并将其鉴定为前颗粒蛋白/原上皮蛋白/大粒蛋白/PCDGF。共免疫沉淀分析显示，前颗粒蛋白与载脂蛋白a -i结合并形成复合物，血清中高密度脂蛋白部分中存在前颗粒蛋白，表明前颗粒蛋白是一种新型载脂蛋白。转染前颗粒蛋白的HEK293细胞条件培养基可增强巨噬细胞上tnf - α和il -1- β的表达，但前颗粒蛋白与HDL或载脂蛋白A-I共孵育可抑制其作用。抗前颗粒蛋白抗体也可降低巨噬细胞上tnf - α和il -1- β的表达。颗粒蛋白作为原蛋白的转化产物，增加了tnf - α和il -1- β的表达，这种作用不受HDL的抑制。结论：我们的研究结果表明HDL对巨噬细胞的抗炎作用可能是由于通过形成复合物抑制前颗粒蛋白向促炎颗粒蛋白的转化。
Aim: HDL has anti-inflammatory effects on macrophages, although the mechanism of action remains unclear. We hypothesized that HDL suppresses the conversion of macrophage-secreted factors into proinflammatory factors via binding, and tried to identify the factor that could form a complex with HDL and/or apolipoprotein (apo) A-I.Methods and Results: In conditioned media obtained from human monocyte-derived macrophages, we found an apo A-I binding protein and identified the protein as progranulin/proepithelin/acrogranin/PCDGF. Co-immunoprecipitation analysis showing that progranulin binds and forms a complex with apo A-I and the presence of progranulin in the HDL fraction in the sera indicated that progranilin is a novel apolipoprotein. Conditioned media of HEK293 cells transfected with progranulin augmented the expression of TNF-alpha and IL-1-beta on macrophages, but these effects of progranulin were inhibited by co-incubation with HDL or apo A-I. Anti-progranulin antibodies also reduced the expression of TNF-alpha and IL-1-beta on macrophages. Granulins as conversion products derived from progranilin increased TNF-alpha and IL-1-beta expression and the effects were not suppressed by HDL.Conclusions: Our results suggest that the anti-inflammatory effects of HDL on macrophages might be due to suppression of the conversion of progranulin into proinflammatory granulins by forming a complex.