Lafutidine inhibits Helicobacter pylori-induced interleukin-8 production in human gastric epithelial cells.
OBJECTIVE
Attachment of Helicobacter pylori to gastric epithelial cells leads to the production of chemokines, such as interleukin-8 (IL-8), which in turn activate and recruit neutrophils to the site of infection. Lafutidine [(+/-)-2-(furfurylsulfinyl)-N-(4-(4-(piperidinomethyl)-2-pyridyl)oxy-(Z)-2-butenyl)acetamide] is a new type of antiulcer drug that possesses an antisecretory action as well as gastroprotective activity, independent of its antisecretory action. In the present study, we examined the effects of lafutidine on H. pylori-induced IL-8 release and H. pylori adhesion to MKN45 cells.


METHODS
MKN45 cells were stimulated with H. pylori, tumor necrosis factor (TNF)-alpha, or IL-1beta, then IL-6 and IL-8 levels in the culture supernatants were determined with a specific enzyme-linked immunosorbent assay kit.


RESULTS
Lafutidine significantly inhibited both the release of IL-8 induced by H. pylori and the adhesion of H. pylori to cells in a dose-dependent manner. These properties of lafutidine are unrelated to the blockade of histamine H(2)-receptors, because the same effects have not been observed with other H(2)-receptor antagonists, such as cimetidine and famotidine. Lafutidine also significantly inhibited H. pylori-induced IL-6 release. Both TNF-alpha and IL-1beta-induced IL-8 releases, conversely, were little affected by lafutidine up to a concentration of 10(-5) M.


CONCLUSIONS
These results suggest that lafutidine inhibits IL-8 release by inhibiting H. pylori adherence to gastric epithelial cells, indicating a novel mechanism by which lafutidine protects against the mucosal inflammation associated with H. pylori infection.
Nozawa
Yoshihisa
Y
Pharmacobioregulation Research Laboratory, Taiho Pharmaceutical Co. Ltd, 1-27 Misugidai, Hanno-shi, Saitama 357-8527, Japan. y-nozawa@taiho.co.jp
Nishihara
Katsushi
K
Akizawa
Yushiro
Y
Orimoto
Naoki
N
Nakano
Motoko
M
Uji
Tatsuya
T
Ajioka
Hirofusa
H
Kanda
Atsuhiro
A
Matsuura
Naosuke
N
Kiniwa
Mamoru
M
D000081:Acetamides / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001422:Bacterial Adhesion / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis*; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000081:Acetamides; D000897:Anti-Ulcer Agents; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D010880:Piperidines; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C076948:lafutidine