Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation
ABSTRACT Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1β and TNF-α, in the gastric cancer cells showed that expression of IL-1β, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1β gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1β gene in gastric epithelial cells.
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ABSTRACT: Helicobacter pylori infection is related to gastric cancer development, and chronic inflammation is presumed to be the main cause. The aim of the present study was to evaluate the influence of H. pylori cagA, vacA, iceA, and babA genotypes on COX-2, IL-1beta, and IL-8 expression. Of the 217 patients included in the study, 26 were uninfected, 127 had chronic gastritis and were H. pylori-positive, and 64 had gastric cancer. Bacterial genotypes were evaluated by polymerase chain reaction (PCR), and the expression values were determined by quantitative real-time PCR and immunohistochemistry. An association was found between the infection with cagA, vacA s1m1 strains and gastric cancer development. Regarding the 3' region of the cagA gene, we also found an association between the infection with cagA EPIYA-ABCCC strains and clinical outcome. Higher levels of IL-8, IL-1beta, and COX-2 were detected in gastric mucosa from infected patients with chronic gastritis, and they were also associated with the infection by cagA, vacA s1m1 strains. The IL-8 and IL-1beta levels decrease significantly from chronic gastritis to gastric cancer, while the relative expression remained unaltered when COX-2 expression was analyzed among patients with gastritis and cancer. Since inflammatory response to H. pylori infection plays an important role in cellular proliferation and gastric mucosal damage, the up-regulation of IL-1beta, IL-8, and COX-2 in patients with chronic gastritis has an important clinical implication in gastric carcinogenesis.Scandinavian Journal of Gastroenterology 12/2008; 44(2):153-61. DOI:10.1080/00365520802530853 · 2.36 Impact Factor
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ABSTRACT: To elucidate the relationship between local immunocompetent cells and prognosis of human hepatocellular carcinoma (HCC) after resection. HE staining and immunohistochemical study were carried out on specimens from patients underwent surgical resection. Local immunocompetent cells, such as dendritic cells (DCs), memory T cells, CD3+ T lymphocytes and CD8+ T lymphocytes, were counted and their relationships with tumor-free survival rate were analyzed by grouping DCs with the T lymphocytes retrospectively. The number grade of infiltrating immunocompetent cells in HCC nodules and pericancerous tissues under HE staining had no significant correlation with tumor-free survival time (P=0.054, 0.071, respectively). DCs were mainly among tumor cells, encircling tumor cells with their pseudopodia and were in contact with T lymphocytes. A certain number of DCs in HCC nodules (> or =25/10HPF) statistically correlated to tumor-free survival time (P=0.005), while a certain number of DCs in pericancerous tissues (> or =28/10HPF) had no correlation with tumor-free survival time (P=0.329). The number of memory T cells, CD3+ T lymphocytes and CD8+ T lymphocytes in HCC nodules strongly correlated to tumor-free survival time (P=0.003, 0.005, 0.037, respectively). The tumor-free survival rate curves revealed that the more DCs or together with memory T cells/CD3+ T lymphocytes or that the more CD8+ T lymphocytes were detected in HCC nodules, the better the prognosis would be. Marked infiltration of DCs in HCC nodules was closely related to the prognosis of HCC after surgical resection and can be served as a predictive index for recurrence and metastasis of HCC.Journal of Cancer Research and Clinical Oncology 06/2006; 132(5):293-301. DOI:10.1007/s00432-006-0075-y · 3.08 Impact Factor
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ABSTRACT: Epidermal Langerhans cells (LC) and the cells into which they mature are believed to play a pivotal role in cutaneous immune function. The induction phase of contact sensitization is associated with the migration of LC from the skin and their accumulation as dendritic cells (DC) in lymph nodes draining the site of exposure. We have demonstrated previously that tumour necrosis factor α (TNF-α), an epidermal cytokine produced by keratinocytes, provides one signal for LC migration. We describe here experiments designed to evaluate the influence of interleukin 1β (IL-1β), a product exclusively of LC in murine epidermis, on LC migration, LC morphology and DC accumulation, and to compare the effects of this cytokine with those of TNF-α. Both cytokines induced a significant reduction in the frequency of epidermal LC and the arrival of DC in draining lymph nodes. Changes in both parameters were induced more rapidly following intradermal administration of TNF-α than were observed after treatment with IL-1β. However, the reduction in LC frequency was more persistent with IL-1β. Both cytokines caused the activation of LC, characterized by the acquisition of a more dendritic morphology and the increased expression of Ia molecules. These results demonstrate that IL-1β and TNF-α can each stimulate the migration of epidermal LC, but that the changes induced by these cytokines are not identical.Archives for Dermatological Research 04/1997; 289(5):277-284. DOI:10.1007/s004030050193 · 1.90 Impact Factor