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-alpha 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.
Aged ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Humans ; Male ; Middle Aged ; Monocytes/metabolism ; Neutrophils/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor, Member 14/*blood ; Stomach Neoplasms/*blood/metabolism ; Tumor Necrosis Factor Ligand Superfamily Member 14/blood

Herpes virus entry mediator (HVEM) is a newly discovered member of the tumor necrosis factor receptor (TNFR) superfamily that has a role in herpes simplex virus entry, in T cell activation and in tumor immunity. We generated mAb against HVEM and detected soluble HVEM (SHVEM) in the sera of patients with various autoimmune diseases. HVEM was constitutively expressed on CD4(+)and CD8(+)T cells, CD19(+)B cells, CD14(+)monocytes, neutrophils and dendritic cells. In three-way MLR, mAb 122 and 139 were agonists and mAb 108 had blocking activity. An ELISA was developed to detect sHVEM in patient sera. sHVEM levels were elevated in sera of patients with allergic asthma, atopic dermatitis and rheumatoid arthritis. The mAbs discussed here may be useful for studies of the role of HVEM in immune responses. Detection of soluble HVEM might have diagnostic and prognostic value in certain immunological disorders.
Animals ; Antibodies, Monoclonal/immunology ; Antibody Specificity ; Arthritis, Rheumatoid/blood/immunology ; Asthma/blood/immunology ; Autoimmune Diseases/*blood/immunology ; Cell Division ; Cell Line ; Dermatitis, Atopic/blood/immunology ; Female ; Flow Cytometry ; Humans ; Hypersensitivity/*blood/immunology ; Lymphocyte Culture Test, Mixed ; Mice ; Mice, Inbred BALB C ; Receptors, Tumor Necrosis Factor/*blood/immunology ; Receptors, Tumor Necrosis Factor, Member 14 ; Receptors, Virus/*blood/immunology ; Solubility