Clinical Experimental Oncology Laboratory, National Cancer Centre, Bari Italy.
Immunopharmacol Immunotoxicol. 2012 Oct;34(5):858-65. doi: 10.3109/08923973.2012.665461. Epub 2012 Mar 8.
Upregulation of inflammatory responses in the brain is associated with a number of neurodegenerative diseases. Microglia are activated in neurodegenerative diseases, producing pro-inflammatory mediators. Critically, lipopolysaccharide (LPS)-induced microglial activation causes dopaminergic neurodegeneration in vitro and in vivo. The signaling mechanisms triggered by LPS to stimulate the release of pro-inflammatory mediators in microglial cells are still incompletely understood. To further explore the mechanisms of LPS-mediated inflammatory response of microglial cells, we studied the role of phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathways known to be activated by toll-like receptor-4 signaling through LPS. In the current study, we report that the activation profile of LPS-induced pAkt activation preceded those of LPS-induced NF-κB activation, suggesting a role for PI3K/Akt in the pathway activation of NF-κB-dependent inflammatory responses of activated microglia. These results, providing the first evidence that PI3K dependent signaling is involved in the inflammatory responses of microglial cells following LPS stimulation, may be useful in preventing inflammatory based neurodegenerative processes.
脑内炎症反应的上调与许多神经退行性疾病有关。小胶质细胞在神经退行性疾病中被激活，产生促炎介质。关键的是，脂多糖（LPS）诱导的小胶质细胞激活导致体外和体内多巴胺能神经退行性变。LPS 触发的信号机制，以刺激小胶质细胞中促炎介质的释放，仍不完全了解。为了进一步探讨 LPS 介导的小胶质细胞炎症反应的机制，我们研究了磷脂酰肌醇 3-激酶（PI3K）/Akt 信号转导通路的作用，该通路已知通过 LPS 激活 Toll 样受体 4 信号而被激活。在本研究中，我们报告 LPS 诱导的 pAkt 激活的激活谱先于 LPS 诱导的 NF-κB 激活，表明 PI3K/Akt 在 LPS 刺激后激活小胶质细胞 NF-κB 依赖性炎症反应的途径中起作用。这些结果首次提供了证据，表明 PI3K 依赖性信号参与 LPS 刺激后的小胶质细胞炎症反应，这可能有助于预防基于炎症的神经退行性过程。
