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


METHODS
MKN45 and HUVEC were stimulated with H. pylori water extract (HPE) and IL-1beta, respectively, and nuclear factor kappa B (NFkappaB) 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-1beta induced a significant increase in IL-8 production by MKN45 and HUVEC, respectively, along with NFkappaB 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 NFkappaB activation in vascular endothelial cells and gastric epithelial cells, and partly by modulating the calcium concentration of PMN.
Handa
O
O
Department of Biomedical Safety Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokouji, Kamigyo-ku, Kyoto, Japan, 602-8566.
Yoshida
N
N
Fujita
N
N
Tanaka
Y
Y
Ueda
M
M
Takagi
T
T
Kokura
S
S
Naito
Y
Y
Okanoue
T
T
Yoshikawa
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D064747:Lansoprazole; D008025:Ligases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D009853:Omeprazole / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D016328:NF-kappa B; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; D009853:Omeprazole; D002118:Calcium