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Infection and Immunity, August 1999, p. 3893-3899, Vol. 67, No. 8
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Multiple Genes in the Left Half of the cag Pathogenicity Island of Helicobacter pylori Are Required for Tyrosine Kinase-Dependent Transcription of Interleukin-8 in Gastric Epithelial Cells

Shude D. Li,1,dagger Dangeruta Kersulyte,2 Ivan J. D. Lindley,3 Beena Neelam,1 Douglas E. Berg,2 and Jean E. Crabtree1,*

Molecular Medicine Unit, St. James's University Hospital, Leeds LS9 7TF, United Kingdom1; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631102; and Novartis Research Institute, A-1235 Vienna, Austria3

Received 4 February 1999/Returned for modification 30 March 1999/Accepted 28 April 1999

Helicobacter pylori strains that contain the cag pathogenicity island (PAI) elicit increased synthesis of gastric C-X-C chemokines, promote neutrophilic infiltration into the gastric epithelium, and stimulate the synthesis of interleukin-8 (IL-8) in cultured gastric epithelial cells. To investigate the effects of cag PAI genes on the transcription of the IL-8 gene, the Kato-3 gastric epithelial cell line was stably transfected with plasmid DNA containing the IL-8 gene promoter fused to a luciferase reporter gene. The resulting reporter cell line, L5F11, was used to monitor the effects of infection in cell culture by H. pylori 26695 and isogenic derivatives with null mutations in genes in the cag PAI on transcription of the IL-8 gene. We found that null mutations in eight open reading frames, including homologs of the Agrobacterium virB9, virB10, and virB11 genes, in the left half of the cag PAI abrogated the induction of IL-8 gene transcription. Further studies with the L5F11 cell line showed that IL-8 gene transcription induced by H. pylori was blocked by the protein tyrosine kinase inhibitor herbimycin A but not by the protein kinase C inhibitor calphostin C or by the protein kinase G inhibitor KT5823. IL-8 gene transcription in L5F11 cells could also be induced by the cytokine tumor necrosis factor alpha (TNF-alpha ) without exposure to H. pylori. This TNF-alpha -induced IL-8 transcription was inhibited by the protein kinase A inhibitor H7, which had no significant effect on H. pylori-induced IL-8 transcription. These studies show that multiple genes in the left half of the cag PAI are essential for the transcription of the IL-8 gene in gastric epithelial cells and that this depends on protein tyrosine kinase activation.

* Corresponding author. Mailing address: Level 7, Clinical Sciences Building, St. James's University Hospital, Leeds LS9 7TF, United Kingdom. Phone: 44-113-2065267. Fax: 44-113-2429722. E-mail: msjjc{at}stjames.leeds.ac.uk.

dagger Present address: Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, People's Republic of China.

Infection and Immunity, August 1999, p. 3893-3899, Vol. 67, No. 8
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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