Abstract
The development of gastric cancer (GC) is closely related to chronic inflammation caused by Helicobacter pylori infection, and herpes virus entry mediator (HVEM) is a receptor expressed on the surface of leukocytes that mediates potent inflammatory responses in animal models. However, the role of HVEM in human GC has not been studied. Previously, we showed that the interaction of HVEM on human leukocytes with its ligand LIGHT induces intracellular calcium mobilization, which results in inflammatory responses including induction of proinflammatory cytokine production and anti-bacterial activities. In this study, we report that leukocytes from GC patients express lower levels of membrane HVEM (mHVEM) and have lower LIGHT-induced bactericidal activities than those from healthy controls (HC). In contrast, levels of soluble HVEM (sHVEM) in the sera of GC patients were significantly higher than in those of HC. We found that monocyte membrane-bound HVEM is released into the medium when cells are activated by proinflammatory cytokines such as TNF-α and IL-8, which are elevated in the sera of GC patients. mHVEM level dropped in parallel with the release of sHVEM, and release was completely blocked by the metalloprotease inhibitor, GM6001. We also found that the low level of mHVEM on GC patient leukocytes was correlated with low LIGHT-induced bactericidal activities against H. pylori and S. aureus and production of reactive oxygen species. Our results indicate that mHVEM on leukocytes and sHVEM in sera may contribute to the development and/or progression of GC.
Highlights
It is well established that inflammation plays critical roles in the development of cancer and metastases
gastric cancer (GC) patient leukocytes have reduced levels of membrane herpes virus entry mediator (HVEM). It has previously been demonstrated by this research group that HVEM was expressed on the membranes of T-cells, B-cells, monocytes and neutrophils isolated from human peripheral blood (Heo et al, 2006)
These results indicate that GC patient leukocytes have reduced activity of HVEM-mediated clearance of H. pylori infection in Ectodomain shedding regulates the activity of a number of transmembrane proteins
Summary
It is well established that inflammation plays critical roles in the development of cancer and metastases. Inflammation is caused by many agents including microbial infections, autoimmune diseases and obesity, and involves complex interactions between proinflammatory cytokines and cells (Mantovani et al, 2008). Tumor necrosis factor α (TNF-α) is one of the most potent proinflammatory cytokines and is involved in the pathogenesis of many inflammatory diseases and tumors (Balkwill, 2009). TNF-α and its receptors have long been targets in the treatment of a variety of human diseases. By-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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