IAI Accepts, published online ahead of print on 19 October 2009

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Infect. Immun. doi:10.1128/IAI.00762-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Helicobacter pylori promotes the production of TSLP by gastric epithelial cells and induces DC-mediated inflammatory Th2 responses

Masahiro Kido, Junya Tanaka, Nobuhiro Aoki, Satoru Iwamoto, Hisayo Nishiura, Tsutomu Chiba, and Norihiko Watanabe^*

Department of Gastroenterology and Hepatology, Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

^* To whom correspondence should be addressed. Email: norihiko{at}kuhp.kyoto-u.ac.jp.

Helicobacter pylori (H. pylori) colonize in the stomach and induce strong, specific local and systemic humoral and cell-mediated immunity, resulting in the development of chronic gastritis in humans. Although H. pylori-induced chronic atrophic gastritis is characterized by marked infiltration of T helper type (Th)1 cytokine-producing CD4⁺ T cells, almost all of the inflamed gastric mucosae also contain focal lymphoid aggregates with germinal centers. In addition, typical H. pylori-induced chronic gastritis in children, called follicular gastritis, is characterized by B-cell follicle formation in the gastric mucosa. The aim of this study is to examine whether thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine inducing dendritic cell (DC)-mediated inflammatory Th2 response, is involved in Th2 responses triggering B cell activation in H. pylori-induced gastritis. Here we show that H. pylori triggered human gastric epithelial cells to produce TSLP together with the DC-attracting chemokine MIP-3 and B cell activating factor BAFF. After DCs were incubated with supernatants from H. pylori-infected epithelial cells, the conditioned cells expressed high levels of costimulatory molecules, such as CD80, and triggered naïve CD4⁺ T cells to produce high levels of the Th2 cytokines interleukin-4 and interleukin-13 and of inflammatory cytokines tumor necrosis factor- and interferon-. In contrast, after incubation of the supernatants with the neutralizing antibodies to TSLP, the conditioned DCs did not prime T cells to produce high levels of Th2 cytokines. These results, together with the finding that TSLP was expressed by the epithelial cells of human follicular gastritis, suggest that H. pylori can directly trigger epithelial cells to produce TSLP. It also suggests that TSLP-mediated DC activation may be involved in Th2 responses triggering B cell activation in H. pylori-induced gastritis.