Abstract
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-κB (NF-κB), we also examined the effect of polaprezinc on NF-κB 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-κB activity was analyzed by electrophoretic mobility shift assay. Western blot analysis with anti-phospho-IκB-α antibody was performed to assess IκB-α phosphorylation. Polaprezinc-suppressed IL-8 secretion induced by tumor necrosis factor α (TNF-α) or IL-1β in a dose-dependent manner. IL-8 mRNA expression also was inhibited by polaprezinc. NF-κB activation in response to TNF-α, IL-1β, phorbol ester, and H2O2 was down-regulated by polaprezinc. Western blot analysis showed inhibition of TNF-α-induced IκB-α 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.
Footnotes
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Send reprint requests to: Tadahito Shimada, M.D., Ph.D., Second Department of Internal Medicine, Dokkyo University School of Medicine, Kita-kobayashi 880, Mibu, Tochigi 321-0293, Japan. E-mail:tshimada{at}dokkyomed.ac.jp
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↵1 This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture in Japan. Part of this work was presented at the annual meeting of the American Gastroenterological Association in New Orleans, Louisiana, May 1998, and was published in abstract form (Gastroenterology114:A1084, 1998).
- Abbreviations:
- IL
- interleukin
- NF-κB
- nuclear factor κB, AP-1, activating protein 1
- TNF-α
- tumor necrosis factor α
- PMA
- phorbol-12 myristate-13 acetate
- SSC
- standard saline citrate
- DTT
- dithiothreitol
- PCR
- polymerase chain reaction
- PMSF
- phenylmethylsulfonyl fluoride
- TBST
- Tris-buffered saline/Tween 20
- EMSA
- electrophoretic mobility shift assay
- Received February 16, 1999.
- Accepted June 10, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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