Slomiany B L, Slomiany A
Research Center University of Medicine and Dentistry of New Jersey Newark, NJ 07103-2400, USA.
J Physiol Pharmacol. 2007 Mar;58(1):117-30.
Activation of cytosolic phospholipase A(2) (cPLA(2)) by bacterial LPS for the rapid release of arachidonic acid from membrane phospholipids is considered a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection. In this study, we report on the role of leptin in modulation of the detrimental consequences of H. pylori LPS-induced cPLA(2) activation that result in the disturbances in gastric mucin synthesis. Employing gastric mucosal cells labeled with [(3)H] arachidonic acid, we show that H. pylori LPS-induced cPLA(2) activation, associated with up-regulation in apoptosis and PAF generation, and the impairment in gastric mucin synthesis, was subject to a dose-dependent suppression by leptin, as well as the inhibition by MAFP, a specific inhibitor of cPLA(2). A potentiation in the countering capacity of leptin on the LPS-induced up-regulation in apoptosis, arachidonic acid release and PAF generation was attained in the presence of ERK inhibitor, PD98059, while PI3K inhibitor, wortmannin had no effect. On the other hand, the prevention by leptin of the LPS detrimental effect on mucin synthesis was subject to suppression by wortmannin, an inhibitor of PI3K as well as the inhibitor of ERK, PD98059. Moreover, potentiation in the effect of leptin on the LPS-induced decrease in mucin synthesis was attained with cPLA(2) inhibitor, MAFP as well as PAF receptor antagonist, BN52020. The results of our findings point to H. pylori LPS-induced ERK-dependent cPLA(2) activation as a critical factor influencing the level of PAF generation, and hence the extent of pathological consequences of H. pylori infection on the synthesis of gastric mucin. Furthermore, we show that leptin counters the pathological consequences of H. pylori-induced cPLA(2) activation on gastric mucin synthesis through the involvement in signaling events controlled by MAPK/ERK and PI3K pathways.
细菌脂多糖（LPS）激活胞质磷脂酶A2（cPLA2），促使膜磷脂中的花生四烯酸快速释放，这被认为是血小板激活因子（PAF）生成过程中的关键步骤，PAF被认为是细菌感染引发炎症事件的最直接介质。在本研究中，我们报告了瘦素在调节幽门螺杆菌LPS诱导的cPLA2激活的有害后果中的作用，该激活会导致胃黏液合成紊乱。使用用[³H]花生四烯酸标记的胃黏膜细胞，我们发现幽门螺杆菌LPS诱导的cPLA2激活与细胞凋亡上调和PAF生成相关，以及胃黏液合成受损，瘦素对其具有剂量依赖性抑制作用，cPLA2的特异性抑制剂MAFP也有抑制作用。在存在ERK抑制剂PD98059的情况下，瘦素对LPS诱导的细胞凋亡上调、花生四烯酸释放和PAF生成的对抗能力增强，而PI3K抑制剂渥曼青霉素没有效果。另一方面，瘦素对LPS对黏液合成的有害作用的预防受到渥曼青霉素（一种PI3K抑制剂以及ERK抑制剂PD98059）的抑制。此外，cPLA2抑制剂MAFP以及PAF受体拮抗剂BN52020可增强瘦素对LPS诱导的黏液合成减少的作用。我们的研究结果表明，幽门螺杆菌LPS诱导的ERK依赖性cPLA2激活是影响PAF生成水平的关键因素，因此也是幽门螺杆菌感染对胃黏液合成的病理后果程度的关键因素。此外，我们表明瘦素通过参与由MAPK/ERK和PI3K途径控制的信号事件来对抗幽门螺杆菌诱导的cPLA2激活对胃黏液合成的病理后果。
