Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP-1/JE in monocytes and microglial cells.
Beta-amyloid (25-35) peptide and IFN-gamma synergistically induce the production of the chemotactic cytokine MCP-1/JE in monocytes and microglial cells.
复制标题
β-淀粉样蛋白 (25-35) 肽和 IFN-γ 协同诱导单核细胞和小胶质细胞中趋化细胞因子 MCP-1/JE 的产生。
作者：
L. Meda;S. Bernasconi;C. Bonaiuto;S. Sozzani;D. Zhou;L. Otvos;A. Mantovani;F. Rossi;M. Cassatella
参与衰老和阿尔茨海默病特征性老年斑发展的分子机制知之甚少。在这项研究中，我们研究了是否人单核细胞和小鼠小胶质细胞刺激的活性片段淀粉样β蛋白（Abeta（25-35））表达单核细胞趋化蛋白-1（MCP-1）/JE。我们表明，在与Abeta（25-35）孵育后，人单核细胞积累MCP-1 mRNA并产生显著量的MCP-1。A β（25-35）对MCP-1分泌的作用既不被乱序类似物模仿，也不受硫酸多粘菌素B的影响，即使后者几乎完全消除了LPS对MCP-1表达的作用。用Abeta（25-35）刺激的小鼠小胶质细胞也表达高水平的JE mRNA（MCP-1的小鼠对应物）并释放生物活性趋化因子。此外，我们报道IFN-γ与Abeta（25-35）在人单核细胞或鼠小胶质细胞中显著协同，并且Abeta（25-35）加/减IFN-γ介导的MCP-1 mRNA的早期诱导不需要新的蛋白质合成。最后，我们提供的证据表明，Abeta（25-35）和Abeta加IFN-γ诱导的MCP-1的产生在很大程度上是由内源性TNF-α以自分泌方式介导的。总之，我们的研究结果揭示了Abeta的另一种新的生物学作用（25-35），并可能有助于更好地理解单核吞噬细胞募集和激活淀粉样蛋白沉积的机制。
The molecular mechanisms involved in the development of senile plaques characteristic of aging and Alzheimer's disease are poorly understood. In this study, we examined whether human monocytes and murine microglial cells stimulated with the active fragment of amyloid beta-protein (Abeta(25-35)) express the monocyte chemotactic protein-1 (MCP-1)/JE. We show that upon incubation with Abeta(25-35), human monocytes accumulate MCP-1 mRNA and produce significant amounts of MCP-1. The effect of Abeta(25-35) on MCP-1 secretion was neither mimicked by a scrambled analogue nor affected by polymyxin B sulfate, even though the latter almost completely abolished the effect of LPS on MCP-1 expression. Murine microglial cells stimulated with Abeta(25-35) also expressed high levels of JE mRNA (the murine counterpart of MCP-1) and released bioactive chemotactic factors. In addition, we report that IFN-gamma significantly synergizes with Abeta(25-35) either in human monocytes or in murine microglial cells, and that Abeta(25-35) plus/minus IFN-gamma-mediated early induction of MCP-1 mRNA does not require new protein synthesis. Finally, we provide evidence that the Abeta(25-35)- and Abeta plus IFN-gamma-induced production of MCP-1 is, in large part, mediated in an autocrine fashion by endogenous TNF-alpha. Taken together, our findings uncover another novel biologic action of Abeta(25-35) and might help in better understanding the mechanisms underlying mononuclear phagocyte recruitment and activation into amyloid deposits.