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Infection and Immunity, September 2004, p. 5019-5026, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5019-5026.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Protein Kinase Mediates Interleukin 17 (IL-17)-Induced IL-8 Secretion in Helicobacter pylori-Infected Human Gastric Epithelial Cells

Ladislava Sebkova,¹ Antonia Pellicanò,¹ Giovanni Monteleone,² Barbara Grazioli,¹ Giovanni Guarnieri,¹ Maria Imeneo,¹ Francesco Pallone,² and Francesco Luzza^1*

Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro "Magna Graecia," Catanzaro,¹ Dipartimento di Medicina Interna, Università di Roma "Tor Vergata," Rome, Italy²

Received 16 February 2004/ Returned for modification 9 April 2004/ Accepted 13 June 2004

Helicobacter pylori-induced mucosal inflammation results in high production of interleukin 17 (IL-17), a potent inducer of IL-8 in gastric epithelial cells. The aim of this study was to investigate signaling pathways by which IL-17 regulates IL-8 production in human gastric epithelial cells. Activation of mitogen-activated protein (MAP) kinases in both IL-17-stimulated MKN28 cells and epithelial cells isolated from H. pylori-colonized gastric mucosa was assessed by Western blotting. In IL-17-stimulated MKN28 cells the activation of activatior protein 1 (AP-1), nuclear factor (NF)-IL-6, and NF-B was also assessed by electrophoretic mobility shift assay. IL-8 production was evaluated by reverse transcription-PCR and enzyme-linked immunosorbent assay (ELISA) both for IL-17-stimulated MKN28 cells treated with specific MAP kinase inhibitors and gastric biopsy cultures treated with a neutralizing IL-17 antibody. Serum from H. pylori-infected patients was tested for immunoglobulin G response to CagA by ELISA. Treatment of MKN28 cells with IL-17 caused activation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) but not other MAP kinases and had the downstream effects of AP-1 and NF-B activation and IL-8 synthesis. Blocking ERK 1/2 activity inhibited AP-1-mediated, but not NF-B-mediated, IL-8 induction. Enhanced activation of ERK 1/2 was seen in gastric epithelial cells isolated from H. pylori-infected patients in comparison to uninfected controls, and this was associated with high IL-8. These effects were even more pronounced in patients seropositive for CagA than in seronegative ones. In gastric biopsy cultures, the addition of a neutralizing IL-17 antibody decreased ERK 1/2 activation, thus resulting in a significant inhibition of IL-8. In H. pylori-colonized gastric epithelial cells, IL-17-induced IL-8 synthesis is associated with and depends at least in part on the activation of ERK 1/2 MAP kinase.

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* Corresponding author. Mailing address: Dipartimento di Medicina Sperimentale e Clinica, Università di Catanzaro "Magna Graecia," Via T Campanella, 88100 Catanzaro, Italy. Phone: 39 961 771859. Fax: 39 961 772885. E-mail: luzza{at}unicz.it.

Editor: J. F. Urban, Jr.

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Infection and Immunity, September 2004, p. 5019-5026, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5019-5026.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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