Activation by prion peptide PrP106-126 induces a NF-κB-driven proinflammatory response in human monocyte-derived dendritic cells
Activation by prion peptide PrP106-126 induces a NF-κB-driven proinflammatory response in human monocyte-derived dendritic cells
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DOI：
10.1189/jlb.1102521
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发表时间：
2003-07-01
影响因子：
5.5
通讯作者：
Feldman, GM
中科院分区：
文献类型：
--
作者：
Bacot, SM;Lenz, P;Feldman, GM
已证明特定的朊病毒肽可以模拟朊病毒蛋白（PrP）的病理亚型，并在体外和体内诱导神经毒性作用。由于单核细胞被认为在朊病毒疾病的传播和发病机制中起作用，因此这些肽在调节单核细胞功能中的用途正在进行深入研究。在目前的研究中，我们的特点朊病毒肽PrP 106 -126激活特定的信号通路在人类单核细胞来源的树突状细胞（DC）的能力。电泳迁移率变动分析建立了激活的转录因子核因子-κ B在15分钟内曝光，与少至25 μ M的肽。这种信号级联导致炎症细胞因子白细胞介素（IL）-1 β、IL-6和肿瘤坏死因子α（TNF-α）在mRNA和蛋白质水平上调。暴露于PrP 106 -126的DC的表型活化部分是自分泌TNF-α应答的结果，并导致这些细胞诱导淋巴细胞增殖的能力增加。PrP 106 -126对DC的作用是通过与人单核细胞所使用的受体复合物不同的受体复合物引起的，这表明该肽能够与各种细胞类型上的多种受体相互作用。总之，这些数据表明，在朊病毒疾病的发病机制中的DC的参与。
Specific prion peptides have been shown to mimic the pathologic isoform of the prion protein (PrP) and to induce a neurotoxic effect in vitro and in vivo. As monocytic cells are thought to play a role in the transmission and pathogenesis of prion disease, the use of these peptides in regulating monocytic cell function is under intense investigation. In the current study, we characterize the ability of prion peptide PrP106-126 to activate specific signaling pathways in human monocyte-derived dendritic cells (DCs). Electrophoretic mobility shift assays establish the activation of transcription factor nuclear factor-kappaB within 15 min of exposure, with as little as 25 muM peptide. This signaling cascade results in the up-regulation of inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) at the mRNA and protein levels. Phenotypic activation of DCs exposed to PrP106-126 is partly a result of an antocrine TNF-alpha response and results in an increased ability of these cells to induce lymphocyte proliferation. The effects of PrP106-126 on DCs were elicited through a receptor complex distinct from that used by human monocytes, demonstrating the ability of this peptide to interact with a multiplicity of receptors on various cell types. Together, these data suggest an involvement of DCs in prion disease pathogenesis.