Anti-inflammatory effects of IL-17A on Helicobacter pylori-induced gastritis
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.
Section snippets
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.
References (25)
- et al.
Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17
J. Biol. Chem.
(2003) - et al.
Interleukin-17 family members and inflammation
Immunity
(2004) - et al.
Involvement of IL-17A in the pathogenesis of DSS-induced colitis in mice
Biochem. Biophys. Res. Commun.
(2008) - et al.
A standardized mouse model of Helicobacter pylori infection: introducing the Sydney strain
Gastroenterology
(1997) - et al.
Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models
Gastroenterology
(1984) - et al.
Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker
J. Invest. Dermatol.
(1982) - et al.
Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice
Clin. Immunol.
(2004) - et al.
TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties
Annu. Rev. Immunol.
(1989) - et al.
Helicobacter pylori-induced mucosal inflammation is Th1 mediated and exacerbated in IL-4, but not IFN-gamma, gene-deficient mice
J. Immunol.
(2000) - et al.
The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice
J. Immunol.
(2001)