Polaprezinc down-regulates proinflammatory cytokine-induced nuclear factor-kappaB activiation and interleukin-8 expression in gastric epithelial cells.
Gastric epithelial chemokine response is a primary factor in the induction of gastric inflammation associated with Helicobacter pylori infection. Because sustained inflammation is a risk for gastric mucosal damage, agents that down-regulate inflammatory responses may be of therapeutic significance. We examined the effect of polaprezinc, a potent antiulcer agent, on proinflammatory cytokine-induced interleukin (IL)-8 expression in gastric epithelial cells. Because IL-8 expression is regulated by the transcription factor nuclear factor-kappaB (NF-kappaB), we also examined the effect of polaprezinc on NF-kappaB activity. MKN28 cells were used as a model of gastric epithelial cells. Secreted IL-8 was quantified by IL-8 specific enzyme-linked immunosorbent assay, and IL-8 mRNA expression was examined by Northern blot analysis. NF-kappaB activity was analyzed by electrophoretic mobility shift assay. Western blot analysis with anti-phospho-IkappaB-alpha antibody was performed to assess IkappaB-alpha phosphorylation. Polaprezinc-suppressed IL-8 secretion induced by tumor necrosis factor alpha (TNF-alpha) or IL-1beta in a dose-dependent manner. IL-8 mRNA expression also was inhibited by polaprezinc. NF-kappaB activation in response to TNF-alpha, IL-1beta, phorbol ester, and H(2)O(2) was down-regulated by polaprezinc. Western blot analysis showed inhibition of TNF-alpha-induced IkappaB-alpha phosphorylation in the presence of polaprezinc. Collectively, these results suggest that polaprezinc is a novel type of anti-inflammatory agent that down-regulates inflammatory responses of gastric mucosal cells.
Shimada
T
T
Second Department of Internal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. tshimada@dokkyomed.ac.jp
Watanabe
N
N
Ohtsuka
Y
Y
Endoh
M
M
Kojima
K
K
Hiraishi
H
H
Terano
A
A
D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002336:Carnosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009942:Organometallic Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013270:Stomach / Q000166:cytology / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017967:Zinc Compounds
D000897:Anti-Ulcer Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009942:Organometallic Compounds; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D017967:Zinc Compounds; C061957:polaprezinc; D000072000:NF-KappaB Inhibitor alpha; D002336:Carnosine