Molecular mechanisms involved in anti-inflammatory effects of proton pump inhibitors

Abstract.

Objective

Interleukin (IL)-8 has been reported to participate in neutrophil infiltration in Helicobacter pylori (H. pylori)-induced gastritis in humans. In this study, we investigated the anti-inflammatory actions beyond the suppression of acid secretion by proton pump inhibitors (PPI), such as omeprazole and lansoprazole, on IL-8 production by gastric epithelial cells (MKN45) and human umbilical vein endothelial cells (HUVEC) and on the transendothelial migration of polymorphonuclear neutrophils (PMN).

Materials and methods

MKN45 and HUVEC were stimulated with H. pylori water extract (HPE) and IL-1β, respectively, and nuclear factor kappa B (NFκB) activation and subsequent IL-8 production was assessed in the absence or presence of PPI. We also assessed the effect of PPI on IL-8-induced PMN transendothelial migration and on the alteration of cytoplasmic calcium concentration in formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN.

Results

HPE and IL-1β induced a significant increase in IL-8 production by MKN45 and HUVEC, respectively, along with NFκB activation, which was significantly inhibited by PPI. PPI also inhibited the IL-8-induced transendothelial migration of PMN and the fMLP-induced cytosolic calcium increase in PMN.

Conclusions

PPI attenuate PMN-dependent gastric mucosal inflammation partly by interfering with NFκB activation in vascular endothelial cells and gastric epithelial cells, and partly by modulating the calcium concentration of PMN.