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A more recent version of this article appeared on October 1, 2005
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Submitted on May 16, 2005
Revised on June 24, 2005
Accepted on July 13, 2005
*Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030;
Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan
Monitoring Editor: J. Silvio Gutkind
The regulation of Helicobacter pylori induced interleukin (IL)-6 in the gastric epithelium remains unclear. Primary gastric epithelial cells and MKN28 cells were cocultured with H. pylori and its isogenic cag pathogenicity island (PAI) mutant and/or oipA mutants. H. pylori infection induced IL-6 mRNA expression and IL-6 protein production which was further enhanced by the cag PAI and OipA. Luciferase reporter gene assays and electrophoretic mobility shift assays showed that full IL-6 transcription required binding sites for nuclear factor-
B (NF-
B), cAMP response element (CRE), CCAAT/enhancer binding protein (C/EBP) and activator protein (AP)-1. The cag PAI and OipA were involved in binding to NF-
B, AP-1, CRE and C/EBP sites. The cag PAI activated the extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) pathways; OipA activated the p38 pathway. Transfection of dominant negative G-protein confirmed roles for Raf, Rac1 and RhoA in IL-6 induction. Overall, the cag PAI-related IL-6 signal transduction pathway involved Ras/Raf/MEK1/2/ERK/AP-1/CRE pathway and JNK/AP-1/CRE pathway, OipA-related pathway is p38/AP-1/CRE and both the cag PAI and OipA appear to be involved in the RhoA/Rac1/NF-
B pathway. Combination of different pathways by the cag PAI and OipA will lead the maximum IL-6 induction.
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