Slomiany B L, Slomiany A
Research Center, C875, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA,
Inflammopharmacology. 2014 Jun;22(3):169-77. doi: 10.1007/s10787-013-0190-8. Epub 2013 Sep 21.
A peptide hormone, ghrelin, is recognized as an important modulator of gastric mucosal inflammatory responses to Helicobacter pylori through the regulation of Src/Akt-dependent activation of constitutive nitric oxide synthase (cNOS) by phosphorylation. In this study, we report on the role of phosphatidylinositol 3-kinase (PI3K) in the processes of Src/Akt activation in gastric mucosal cells exposed to H. pylori LPS. We demonstrate that cNOS activation through phosphorylation induced by ghrelin is associated with PI3K activation which occurs upstream of cSrc, and that PI3K is required for cSrc activation of Akt. We show further that ghrelin-induced activation of PI3K, as well as that of Src and Akt, was susceptible to suppression by the inhibitors of phospholipase C (U73122) and protein kinase C (BIM). Both these inhibitors also blocked the ghrelin-induced membrane translocation of PI3K and cSrc, whereas the inhibitor of PI3K (LY294002) blocked only the membrane translocation of cSrc. Collectively, our findings suggest that the modulatory influence of ghrelin in countering gastric mucosal responses to H. pylori LPS relies on PI3K activation that depends on PLC/PKC signaling pathway, and that PI3K activity is required for the induction of cSrc/Akt activation.
一种肽类激素——胃饥饿素，通过磷酸化调节Src/Akt依赖的组成型一氧化氮合酶（cNOS）激活，被认为是胃黏膜对幽门螺杆菌炎症反应的重要调节因子。在本研究中，我们报告了磷脂酰肌醇3激酶（PI3K）在暴露于幽门螺杆菌脂多糖（LPS）的胃黏膜细胞中Src/Akt激活过程中的作用。我们证明，胃饥饿素诱导的磷酸化导致的cNOS激活与PI3K激活相关，PI3K激活发生在cSrc上游，且PI3K是Akt的cSrc激活所必需的。我们进一步表明，胃饥饿素诱导的PI3K激活以及Src和Akt的激活，易受磷脂酶C抑制剂（U73122）和蛋白激酶C抑制剂（BIM）的抑制。这两种抑制剂还阻断了胃饥饿素诱导的PI3K和cSrc的膜转位，而PI3K抑制剂（LY294002）仅阻断了cSrc的膜转位。总体而言，我们的研究结果表明，胃饥饿素在对抗胃黏膜对幽门螺杆菌LPS反应中的调节作用依赖于PI3K激活，而PI3K激活取决于PLC/PKC信号通路，且PI3K活性是诱导cSrc/Akt激活所必需的。
