Enhanced expression of CCL20 in human Helicobacter pylori-associated gastritis
Introduction
Helicobacter pylori is one of the most common infections in humans [1], [2]. This noninvasive organism colonizes the gastric epithelium and causes chronic gastritis that is characterized by dense infiltration of neutrophils and mononuclear cells into the lamina propria [3], [4]. H. pylori elicits specific antibodies against various immunogenic proteins derived from the bacterium [5]. Despite the cellular and humoral immune responses, H. pylori infection shows lifelong persistence in the majority of cases [1], [2]. The complex interplay between the bacterium and the host immune reaction is not fully understood.
Chemokines are a family of cytokines that are characterized by their biological ability to attract different cell types through their action on specific receptors, and they play a pivotal role in various immune and inflammatory conditions, including H. pylori-associated gastritis (HAG) [6], [7], [8], [9], [10], [11], [12]. We have previously demonstrated enhancement of mucosal production of interleukin 8 (IL-8), a representative chemoattractant for neutrophils, monocyte chemoattractant protein 1 (MCP-1), and regulated on activation normal T-cell expressed and presumably secreted (RANTES), both of which induce an influx of mononuclear cells, such as macrophages and lymphocytes, in patients with HAG [8]. Mucosal IL-8 concentrations have been associated with the degree of neutrophil infiltration, whereas the MCP-1 and RANTES levels have been shown to be correlated with the grades of mononuclear cell infiltration in H. pylori-infected gastric mucosa [8]. Accumulating evidence has shown that a variety of chemokines are involved in the development of HAG.
Dendritic cells (DCs) are dedicated antigen-presenting cells and function as central mediators between the innate and cognate immune systems [13]. DC trafficking is tightly controlled by differential expression of chemokine ligands and specific receptors; immature DCs that express CC-chemokine receptor 6 (CCR6) migrate towards its exclusive chemokine ligand, CC-chemokine ligand 20 (CCL20, also known as macrophage inflammatory protein 3α, liver and activation-regulated chemokines, or exodus-1) at the inflammatory site, where they capture and process antigens [14], [15]. Nishi et al. have reported that H. pylori infection upregulates CCL20 expression in gastric epithelial cells and induces an influx of DCs into the infected gastric mucosa of mice [10]. Recent studies have shown CCL20 upregulation and recruitment of CCR6-expressing CD3+ cells in gastric mucosa during H. pylori infection in humans [11], suggesting that CCL20 may play a role in HAG through interaction with the corresponding receptor.
The aim of the present study was to determine the role of CCL20 expression in the development of HAG in a relatively large number of subjects. The study was also designed to examine the expression of other lymphoid chemokines, CCL19 and CCL21, which are exclusive ligands for CCR7 expressed on mature type DCs [16], [17]. To determine whether H. pylori infection leads to CCL20 upregulation in vitro, CCL20 expression by gastric epithelial cells infected with diverse H. pylori strains was investigated.
Section snippets
Subjects and tissue samples
Consecutive outpatients who underwent upper gastrointestinal endoscopy for dyspepsia between June 2006 and May 2007 were recruited. The study was approved by the Nagasaki University Ethics Committee. All samples were obtained with the written informed consent of the patients prior to their inclusion, in accordance with the Helsinki Declaration. Exclusion criteria were: age < 18 or > 80 years, pregnancy, body mass index (BMI) > 30 kg/m2, diabetes mellitus, cachectic state (including cancer),
Baseline characteristics
A total of 84 patients (mean age: 64 years; range: 49–80 years), consisting of 58 men and 46 women, was studied. There were 32 current smokers and 37 alcohol drinkers. Based on the rapid urease test and histopathology, 42 subjects each were designated as either positive or negative for H. pylori infection. Baseline characteristics, including age, gender, alcohol intake, smoking habits, and body mass index, were not statistically different between the H. pylori-infected group and the uninfected
Discussion
The present results showed increased local production of CCL20, a representative lymphoid chemokine, in the gastric mucosa of patients infected with H. pylori. Nishi et al. were the first to report the association of H. pylori infection with CCL20 overexpression in murine gastric tissue [10]. Recent studies using RT-PCR showed that CCL20 mRNA expression was upregulated in H. pylori-infected gastric mucosa in humans, though only a small number of patients was examined [11], [12]. In the present
Acknowledgment
J Moss was supported by the intramural research program, NIH, NHLBI.
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