Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44.

Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.

[1]  Yun-ping Zhu,et al.  Identification of metastasis‐associated proteins by proteomic analysis and functional exploration of interleukin‐18 in metastasis , 2003, Proteomics.

[2]  E. Scanziani,et al.  Quantitative Evaluation of Inflammatory and Immune Responses in the Early Stages of Chronic Helicobacter pylori Infection , 2003, Infection and Immunity.

[3]  G. Favre,et al.  Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response. , 2003, International immunology.

[4]  M. Stolte,et al.  Oxidative Stress in Gastric Mucosa of Asymptomatic Humans Infected with Helicobacter pylori: Effect of Bacterial Eradication , 2002, Helicobacter.

[5]  J. Jeon,et al.  The enhanced IL-18 production by UVB irradiation requires ROI and AP-1 signaling in human keratinocyte cell line (HaCaT). , 2002, Biochemical and biophysical research communications.

[6]  K. Agematsu,et al.  IL‐10 enhances B‐cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction , 2002, Clinical and experimental immunology.

[7]  M. Pfeifer,et al.  Tumour necrosis factor‐α induced CD70 and interleukin‐7R mRNA expression in BEAS‐2B cells , 2002, European Respiratory Journal.

[8]  Bryan R. Cullen,et al.  RNA interference: antiviral defense and genetic tool , 2002, Nature Immunology.

[9]  E. Losi,et al.  Correlation between Helicobacter pylori Infection and IL‐18 mRNA Expression in Human Gastric Biopsy Specimens , 2002, Annals of the New York Academy of Sciences.

[10]  D. Yoon,et al.  Enhanced IL-18 expression in common skin tumors. , 2001, Immunology letters.

[11]  T. Majima,et al.  Preoperative serum interleukin‐18 level as a postoperative prognostic marker in patients with gastric carcinoma , 2001, Cancer.

[12]  S. Lee,et al.  Seroepidemiological study of Helicobacter pylori infection in asymptomatic people in South Korea , 2001, Journal of gastroenterology and hepatology.

[13]  A. Koch,et al.  Evidence of IL-18 as a Novel Angiogenic Mediator1 , 2001, The Journal of Immunology.

[14]  C. Wong,et al.  Proinflammatory cytokines (IL‐17, IL‐6, IL‐18 and IL‐12) and Th cytokines (IFN‐γ, IL‐4, IL‐10 and IL‐13) in patients with allergic asthma , 2001, Clinical and experimental immunology.

[15]  Li Zhu,et al.  Non-small Cell Lung Cancer Cyclooxygenase-2-dependent Invasion Is Mediated by CD44* , 2001, The Journal of Biological Chemistry.

[16]  T. Schumacher,et al.  CD27 is required for generation and long-term maintenance of T cell immunity , 2000, Nature Immunology.

[17]  M. Kurimoto,et al.  Endogenous interleukin-18 modulates immune escape of murine melanoma cells by regulating the expression of Fas ligand and reactive oxygen intermediates. , 2000, Cancer research.

[18]  Mamoru Ito,et al.  CD27-Mediated Activation of Murine NK Cells1 , 2000, The Journal of Immunology.

[19]  G. Fantuzzi,et al.  IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  I. McInnes,et al.  A proinflammatory role for IL-18 in rheumatoid arthritis. , 1999, The Journal of clinical investigation.

[21]  N. Rouas-Freiss,et al.  [HLA-G: a tolerance molecule implicated in the escape of tumors from immunosurveillance]. , 1999, Pathologie-biologie.

[22]  H. Okamura,et al.  Inhibition by interleukin 18 of osteolytic bone metastasis by human breast cancer cells. , 1999, Anticancer research.

[23]  J. Pelletier,et al.  Interleukin-1beta-converting enzyme/caspase-1 in human osteoarthritic tissues: localization and role in the maturation of interleukin-1beta and interleukin-18. , 1999, Arthritis and rheumatism.

[24]  J. Dausset,et al.  HLA-G expression in human melanoma cells: protection from NK cytolysis. , 1999, Journal of reproductive immunology.

[25]  P. Malfertheiner,et al.  Helicobacter pylori in gastric lymphoma and carcinoma , 1998 .

[26]  P. Kincade,et al.  The importance of cellular environment to function of the CD44 matrix receptor. , 1997, Current opinion in cell biology.

[27]  H. Okamura,et al.  IFN-gamma-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine natural killer cell clones. , 1996, Journal of immunology.

[28]  D. Gotley,et al.  Alternatively spliced variants of the cell adhesion molecule CD44 and tumour progression in colorectal cancer. , 1996, British Journal of Cancer.

[29]  F. Miedema,et al.  Increased expression of CD80, CD86 and CD70 on T cells from HIV‐infected individuals upon activation in vitro: regulation by CD4+ T cells , 1996, European journal of immunology.

[30]  H. Okamura,et al.  Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. , 1996, Journal of immunology.

[31]  H. Stein,et al.  PHENOTYPIC MODULATION OF HODGKIN AND REED–STERNBERG CELLS BY EPSTEIN–BARR VIRUS , 1996, The Journal of pathology.

[32]  H. Okamura,et al.  Cloning of a new cytokine that induces IFN-γ production by T cells , 1995, Nature.

[33]  F. Marincola,et al.  Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. , 1995, Immunology today.

[34]  E. Tahara.  Molecular biology of gastric cancer , 1995, World journal of surgery.

[35]  M. Blaser,et al.  Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. , 1995, Cancer research.

[36]  R. V. van Lier,et al.  Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation. , 1995, Journal of immunology.

[37]  C. Morimoto,et al.  CD27 is a signal-transducing molecule involved in CD45RA+ naive T cell costimulation. , 1994, Journal of immunology.

[38]  H. Yokozaki,et al.  Gene alterations in intestinal metaplasia and gastric cancer. , 1994, European journal of gastroenterology & hepatology.

[39]  J. Bell,et al.  Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. Fontana,et al.  Protease inhibitors interfere with the transforming growth factor-beta-dependent but not the transforming growth factor-beta-independent pathway of tumor cell-mediated immunosuppression. , 1992, Journal of immunology.

[41]  I. Stamenkovic,et al.  CD44 is the principal cell surface receptor for hyaluronate , 1990, Cell.

[42]  M. Smyth,et al.  Induction of tumor-specific T cell memory by NK cell–mediated tumor rejection , 2002, Nature Immunology.

[43]  G. Offerhaus,et al.  CD44 glycoproteins in colorectal cancer: expression, function, and prognostic value , 1999 .

[44]  S. Rosenberg,et al.  Human melanoma cells do not express Fas (Apo-1/CD95) ligand. , 1999, Cancer research.

[45]  H. Okamura,et al.  Interleukin-18: a novel cytokine that augments both innate and acquired immunity. , 1998, Advances in immunology.

[46]  C. Morimoto,et al.  Generation of plasma cells from peripheral blood memory B cells: synergistic effect of interleukin-10 and CD27/CD70 interaction. , 1998, Blood.

[47]  Ronit Vogt Sionov,et al.  CD44: structure, function, and association with the malignant process. , 1997, Advances in cancer research.

[48]  H. Okamura,et al.  Cloning of a new cytokine that induces IFN-gamma production by T cells. , 1995, Nature.

[49]  G. Favre,et al.  Involvement of CD 70 and CD 80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response , 2022 .