Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide
Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide
复制标题
DOI：
10.4049/jimmunol.171.2.717
复制
发表时间：
2003-07-15
影响因子：
4.4
通讯作者：
Michalek, SM
中科院分区：
文献类型：
--
作者：
Martin, M;Schifferle, RE;Michalek, SM
经证实，牙龈卟啉单胞菌LPS刺激APC可产生某些促炎和抗炎细胞因子。然而，调控这些过程的信号通路目前尚不清楚。在本研究中，我们研究了磷脂酰肌醇3激酶(PI3K)-Akt通路在调节牙龈假单胞菌lps诱导的人单核细胞产生IL-10、IL-12 p40和IL-12 p70中的作用。P. gingivalis LPS通过toll样受体2选择性激活PI3K-Akt通路，抑制该通路导致细胞外信号调节的激酶1/2磷酸化消失，而p38和c-Jun n -末端激酶1/2激酶的激活不受影响。用牙龈卟啉脂多糖刺激单核细胞后对细胞因子产生的分析显示，抑制PI3K通路对IL-10和IL-12的合成有差异调节。IL-10的产生被抑制，而IL-12的水平则被提高。抑制牙龈卟啉卟啉脂多糖介导的PI3K-Akt通路的激活导致NF-kappaB p65的显著增强，这与ikappab - α降解无关。此外，PI3K-Akt通路调节IL-10和IL-12产生的能力似乎是通过选择性抑制细胞外信号调节激酶1/2活性介导的，因为MEK1抑制剂PD98059非常类似wortmannin和LY294002对牙龈假单胞菌lps刺激的单核细胞差异调节IL-10和IL-12产生的作用。这些研究为牙龈卟啉卟啉脂多糖参与PI3K-Akt通路如何影响控制先天免疫和适应性免疫定性和定量方面的关键免疫调节细胞因子的诱导提供了新的见解。
Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.