Interleukin-1beta induces cyclo-oxygenase-2 expression in gastric cancer cells by the p38 and p44/42 mitogen-activated protein kinase signaling pathways.

Abstract

BACKGROUND AND AIMS:

Cyclo-oxygenase-2 (COX-2) is the inducible enzyme in the gastric mucosa responsible for prostaglandin production during inflammation and ulcer healing. The regulation of COX-2 gene expression in gastric epithelial cells is not well understood. In this study, we investigated the effect of interleukin (IL)-1beta on COX-2 expression in the human gastric cancer cell, and explored the signaling pathways involved.

METHODS:

Gastric cancer cell line AGS was treated with IL-1beta or the inhibitors of mitogen-activated protein-Erk kinase (MEK) and p38 mitogen-activated protein (MAP) kinase prior to the addition of IL-1beta. The COX-2 mRNA or protein levels were measured by using RT-PCR or western blot analysis, respectively. Prostaglandin E2 (PGE2) production/secretion was determined by using the prostaglandin E2 EIA assay. The phosphorylation/activation of p44/42 and p38 MAP kinases were determined by using western blot analysis and using phospho-specific antibodies.

RESULTS:

Interleukin-1beta treatment dose- and time-dependently increased COX-2 mRNA and protein expression levels, and enhanced PGE2 production/secretion in AGS cells. In contrast, IL-1beta had no effect on the level of the constitutively expressed COX-1. In parallel to the increase of COX-2, we showed that p44/42 and p38 MAP kinase activities were also upregulated by IL-1beta treatment. To demonstrate the cause-effect relationship, we showed that inhibition of MEK and p38 MAP kinase with specific inhibitors suppressed IL-1beta-mediated increases in COX-2 mRNA and protein levels, and the PGE2 production.

CONCLUSIONS:

Our results demonstrated that in human gastric cancer cells, IL-1beta upregulates the COX-2 gene expression through the activation of MEK/p44/42 and p38 MAP kinases pathway.

• Authors: X M Fan, B C Wong, M C Lin, C H Cho, W P Wang, H F Kung, S K Lam
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 16 Issue 10 Pg. 1098-104 (Oct 2001) ISSN: 0815-9319 [Print] Australia
• PMID: 11686835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• Imidazoles
• Interleukin-1
• Isoenzymes
• Membrane Proteins
• Pyridines
• RNA, Messenger
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Dinoprostone
• SB 203580
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Adenocarcinoma (metabolism)
• Blotting, Western
• Cyclooxygenase 2
• Dinoprostone (biosynthesis, genetics)
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Gene Expression (drug effects)
• Humans
• Imidazoles (pharmacology)
• Interleukin-1 (pharmacology)
• Isoenzymes (genetics, metabolism)
• Membrane Proteins
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Prostaglandin-Endoperoxide Synthases (genetics, metabolism)
• Pyridines (pharmacology)
• RNA, Messenger (biosynthesis)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Stomach Neoplasms (metabolism)
• Tumor Cells, Cultured
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases