Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation.
Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1β and TNF-α, in the gastric cancer cells showed that expression of IL-1β, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1β gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1β gene in gastric epithelial cells.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan. nyamamic-tky@umin.ac.jp
Nobutake
N
Yamamichi
Masashi
M
Oka
Ken-ichi
K
Inada
Maki
M
Konno-Shimizu
Natsuko
N
Kageyama-Yahara
Hideyuki
H
Tamai
Jun
J
Kato
Mitsuhiro
M
Fujishiro
Shinya
S
Kodashima
Keiko
K
Niimi
Satoshi
S
Ono
Yutaka
Y
Tsutsumi
Masao
M
Ichinose
Kazuhiko
K
Koike
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D016480:Helicobacter pylori; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D015854:Up-Regulation
D000897:Anti-Ulcer Agents; D053583:Interleukin-1beta; D015363:Quinolones; D008769:Methylnitronitrosoguanidine; C052785:rebamipide; D000409:Alanine