Research Center, C855, Rutgers School of Dental Medicine, Rutgers, The State University of New Jersey, 110 Bergen Street, PO Box 1709, Newark, NJ, 07103-2400, USA.
Inflammopharmacology. 2017 Aug;25(4):415-429. doi: 10.1007/s10787-017-0360-1. Epub 2017 May 17.
Infection with Helicobacter pylori is a primary culprit in the etiology of gastric disease, and its cell-wall lipopolysaccharide (LPS) is recognized as a potent endotoxin responsible for triggering a pattern of the mucosal inflammatory responses. The engagement by the LPS of gastric mucosal Toll-like receptor 4 (TLR4) leads to initiation of signal transduction events characterized by the activation of mitogen-activated protein kinase (MAPK) cascade, induction of phosphoinositide-specific phospholipase C (PLC)/protein kinase C (PKC)/phosphatidylinositol 3-kinase (PI3K) pathway, and up-regulation in Src/Akt. These signaling events in turn exert their influence over H. pylori-elicited excessive generation of NO and PGE2 caused by the disturbances in nitric oxide synthase and cyclooxygenase isozyme systems, increase in epidermal growth factor receptor transactivation, and the induction in matrix metalloproteinase-9 (MMP-9) release. Interestingly, the extent of gastric mucosal inflammatory response to H. pylori is influenced by a peptide hormone, ghrelin, the action of which relays on the growth hormone secretagogue receptor type 1a (GHS-R1a)-mediated mobilization of G-protein dependent transduction pathways. Yet, the signals triggered by TLR-4 activation as well as those arising through GHS-R1a stimulation converge at MAPK and PLC/PKC/PI3K pathways that form a key integration node for proinflammatory signals generated by H. pylori LPS as well as for those involved in modulation of inflammation by ghrelin. Hence, therapeutic targeting these signals' convergence and integration node could provide a novel and attractive opportunities for developing more effective treatments of H. pylori-related gastric disease.
幽门螺杆菌感染是胃病病因学中的主要罪魁祸首，其细胞壁脂多糖（LPS）被认为是触发黏膜炎症反应模式的有效内毒素。LPS 与胃黏膜 Toll 样受体 4（TLR4）的结合导致信号转导事件的启动，其特征是有丝分裂原激活蛋白激酶（MAPK）级联、诱导磷酯酰肌醇特异性磷脂酶 C（PLC）/蛋白激酶 C（PKC）/磷酸肌醇 3-激酶（PI3K）途径的激活，以及Src/Akt 的上调。这些信号事件反过来又通过干扰一氧化氮合酶和环氧化酶同工酶系统、增加表皮生长因子受体反式激活和诱导基质金属蛋白酶-9（MMP-9）释放，对 H. pylori 引起的过量 NO 和 PGE2 产生产生影响。有趣的是，胃黏膜对 H. pylori 的炎症反应程度受到肽激素胃饥饿素的影响，其作用依赖于生长激素促分泌素受体 1a（GHS-R1a）介导的 G 蛋白依赖转导途径的动员。然而，TLR-4 激活引发的信号以及通过 GHS-R1a 刺激引发的信号都集中在 MAPK 和 PLC/PKC/PI3K 途径上，这些途径形成了由 H. pylori LPS 产生的促炎信号以及由胃饥饿素调节炎症的信号的关键整合节点。因此，针对这些信号的汇聚和整合节点进行治疗可能为开发更有效的治疗 H. pylori 相关胃病的方法提供新的有吸引力的机会。
