Anti-inflammatory effects of IL-17A on Helicobacter pylori-induced gastritis

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Abstract

Helicobacter pylori-induced immune responses are skewed toward a T helper (Th) 1 phenotype. IL-17-producing Th17 cells have recently been discovered, and we examined the role of IL-17A in H. pylori-induced gastritis. Six months after inoculation with H. pylori, the mice received an intraperitoneal injection of recombinant IL-17A, anti-IL-17A antibody or irrelevant IgG2a for 3 days. H. pylori infection markedly increased mRNA for IL-17A. Double immunofluorescence studies showed that IL-17A proteins were expressed on CD4+ T cells, macrophages, and dendritic cells. H. pylori infection elevated mRNAs for IL-12, IFN-γ, and TNF-α with increase in myeloperoxidase activity, whereas it did not affect mRNAs for IL-4 and IL-5. Neutralization of IL-17A elevated mRNAs for IFN-γ and TNF-α, and myeloperoxidase activity, whereas recombinant IL-17A had a tendency to reduce these parameters. In conclusion, IL-17A exerts anti-inflammatory effects on H. pylori-induced gastritis through suppression of Th1 differentiation.

Introduction

Helicobacterpylori is a spiral-shaped gram-negative bacterium that colonizes the human stomach and causes chronic gastritis and peptic ulcers. In response to the pathogenic bacterial products, various types of inflammatory cytokines are produced in the gastric mucosa. The regulation of immune responses has been explained by the balance of T helper (Th) 1 and Th2 cells [1], and immune responses to H. pylori infection are reported to be skewed toward a Th1 phenotype, indicated by a predominance of interferon (IFN)-γ and tumor necrosis factor (TNF)-α[2], [3].

Recently, a novel and unique subset of interleukin (IL) 17-producing Th17 cells, distinct from Th1 and Th2 cells, has been discovered [4], [5], [6]. IL-23 plays a key role in the differentiation of Th17 cells, while IL-12 and IL-4 promote Th1 and Th2 cell differentiation, respectively [7]. More recently, it was found that IL-17 has 6 family members (IL-17A–F), and IL-17A is the prototypic IL-17 family member [8], [9]. IL-17A, also called simply IL-17, exerts proinflammatory effects by stimulation of the production of cytokines and chemokines such as IL-1, IL-6, and monocyte chemoattractant protein-1, and up-regulation of cell adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1.

IL-17A plays an important role in the development of chronic inflammatory diseases, including autoimmune diseases. Nakae et al. demonstrated suppression of collagen-induced arthritis, a rodent model of rheumatoid arthritis, in IL-17-deficient mice [10]. Similarly, Komiyama et al. reported that experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis, was suppressed in IL-17-deficient mice [11]. Furthermore, deletion of the IL-17 receptor gene protected against 2,4,6-trinitrobenzene sulfonic acid-induced colitis [12], and IL-17A knockout mice exhibited marginal tissue damage with less neutrophil infiltration in dextran sodium sulfate (DSS)-induced colitis [13], suggesting that IL-17A has stimulating effects on many types of tissue inflammation, including that of the gastrointestinal tract.

IL-17A has been reported to be consistently increased in Th1-mediated diseases [14], and H. pylori-colonized gastric mucosa contained high levels of IL-17A and showed Th1 immune responses [15], [16], but the role of IL-17A in immune responses to H. pylori infection has not yet been investigated in detail. In this study, we examined the gene expression and role of IL-17A in H. pylori-induced gastritis in mice.

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Materials and methods

Animals. Specific pathogen-free C57BL/6J mice (4 weeks old, 10–15 g) were obtained from Charles River Japan Inc. (Atsugi, Japan). In mouse experiments, all animals were housed in polycarbonate cages with paper-chip bedding in an air-conditioned biohazard room with a 12 h light/12 h dark cycle. All animals had free access to food and water. All experimental procedures were approved by the Animal Care Committee of the Osaka City University Graduate School of Medicine.

Helicobacter pylori preparation

Neutrophil infiltration and cytokine profile in H. pylori-induced gastritis

Six months after inoculation with H. pylori, MPO activity was significantly increased 9.8-fold compared with H. pylori-uninfected mice (Fig. 1A). H. pylori infection significantly elevated expression of mRNA for IL-17A 24.0-fold and also elevated expression of mRNAs for IL-12, IFN-γ, and TNF-α 17.2-, 93.2-, and 10.3-fold, respectively (Fig. 1B). In contrast, infection did not affect mRNA levels for IL-4 and IL-5. These results are compatible with previous reports demonstrating that Th1 immune

Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology in Japan.

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