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Vol. 16, Issue 10, 4954-4966, October 2005

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Regulation of Interleukin-6 Promoter Activation in Gastric Epithelial Cells Infected with Helicobacter pylori

Hong Lu ^*, Jeng Yih Wu ^* , Takahiko Kudo ^*, Tomoyuki Ohno , David Y. Graham ^*, and Yoshio Yamaoka ^*

^* 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

Submitted May 16, 2005; Revised June 24, 2005; Accepted July 13, 2005
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 the Ras/Raf/MEK1/2/ERK/AP-1/CRE pathway and the JNK/AP-1/CRE pathway; the 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 to the maximum IL-6 induction.

Abbreviations used: AP-1, activator protein-1; C/EBP, CCAAT/enhancer binding protein; CRE, cAMP response element; CREB, CRE-binding protein; EMSA, electrophoretic mobility shift assay; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-regulated kinase; IL, interleukin, JNK, Jun-N-terminal kinase; MAPK, mitogen-activated protein kinase; NF, nuclear factor; PAI, pathogenicity island.

Present address: Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Address correspondence to: Yoshio Yamaoka (yyamaoka{at}bcm.tmc.edu).

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