Lorton D, Schaller J, Lala A, De Nardin E
Hoover Arthritis Research Center, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA.
Neurobiol Aging. 2000 May-Jun;21(3):463-73. doi: 10.1016/s0197-4580(00)00092-0.
Evidence suggests that beta-amyloid (Abeta) has chemokine-like properties and may act through formyl chemotactic receptors (FPR) to induce pathophysiologically important functional changes in Alzheimer's disease (AD) microglia. We have shown that Abeta 1-42, fibrillar Abeta 1-40, and Abeta 25-35 potentiate the release of interleukin-1beta (IL-1beta) from LPS activated human THP-1 monocytes [26] and LPS primed rat microglia. Moreover, Abeta-stimulated IL-1beta secretion seems to be receptor mediated because it is calcium dependent and requires activation of specific G-proteins [27]. Thus, we have evaluated the ability of Abeta 1-42 to mimic formyl chemotactic peptides in stimulating IL-1beta release from THP-1 monocytes. Several of the formyl chemotactic peptides and Abeta 1-42 significantly enhanced IL-1beta production in THP-1 monocytes. In contrast, a formyl chemotactic receptor antagonist inhibited Abeta 1-42-induced IL-1beta release from both human THP-1 monocytes and primary rat microglia. Further, primary rat microglia grown in culture expressed FPR as demonstrated by immunocytochemistry. Given the multiple pathophysiologic roles IL-1beta may play in AD, agents that block Abeta interactions with formyl chemotactic receptors on microglia might be important antiinflammatory therapeutic targets.
有证据表明，β-淀粉样蛋白（Aβ）具有趋化因子样特性，可能通过甲酰基趋化受体（FPR）发挥作用，从而在阿尔茨海默病（AD）小胶质细胞中诱导具有病理生理学重要意义的功能变化。我们已经表明，Aβ1-42、纤维状Aβ1-40和Aβ25-35可增强LPS激活的人THP-1单核细胞[26]和LPS预处理的大鼠小胶质细胞中白细胞介素-1β（IL-1β）的释放。此外，Aβ刺激的IL-1β分泌似乎是受体介导的，因为它依赖于钙，并且需要特定G蛋白的激活[27]。因此，我们评估了Aβ1-42在刺激THP-1单核细胞释放IL-1β方面模拟甲酰基趋化肽的能力。几种甲酰基趋化肽和Aβ1-42显著增强了THP-1单核细胞中IL-1β的产生。相比之下，一种甲酰基趋化受体拮抗剂抑制了Aβ1-42诱导的人THP-1单核细胞和原代大鼠小胶质细胞中IL-1β的释放。此外，免疫细胞化学证明，培养的原代大鼠小胶质细胞表达FPR。鉴于IL-1β可能在AD中发挥多种病理生理作用，阻断Aβ与小胶质细胞上甲酰基趋化受体相互作用的药物可能是重要的抗炎治疗靶点。
