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TRAILing gastrointestinal pathogenesis

The role of cell kinetics in Helicobacter pylori -related gastrointestinal disorders has been extensively investigated over the past decade. Epithelial cell death is frequently increased and followed by enhanced cell proliferation and cell turnover in H. pylori -infected humans and animals. The enhanced replication of gastric epithelium might increase the risk of replication error, leading to cell transformation. To form neoplastic colonies, the transformed cells must survive stimuli that cause programmed cell death (PCD or apoptosis). During development, cell replication overcomes PCD in neoplastic foci. Immunologic responses are also regulated by PCD and lymphocyte cell replication, for example. Several factors determine the balance between PCD and cell replication in the stomach, including H. pylori , 1–8 ammonia, 9,10 cyclooxygenases, 11–13 and tumor necrosis factor (TNF)a . 14–17 Several other factors also have an important role in PCD and remain to be investigated in view of gastrointestinal pathology. In this issue of the Journal, Koyama examines the expression of TNF-related apoptosis inducing ligand (TRAIL) and its receptors in gastric mucosa with H. pylori infection. 18 The expression of TRAIL, DR4/ DR5 receptors, and DcR2 decoy receptors in gastric epithelial cells and lymphocytes was enhanced in H. pylori -positive subjects as compared with H. pylori negative subjects. In addition, both gastric epithelial cells and gastric lymphocytes led to PCD, and proportions of CD19 + B cells and CD3 + T cells (particularly CD8 + CD11b – cells and CD4 + CD62L – cells) were expanded in H. pylori -positive subjects. His finding might be of importance because TRAIL, together with other TNF family ligands, has a significant influence on not only tumorigenesis but also the population of lymphocytes in response to the bacteria. Here, possible roles of TRAIL and the other TNF-like ligands in gastrointestinal pathology are discussed. TNFa is a proinflammatory cytokine that has an important role in immunity and inflammation, and in the control of cell proliferation, differentiation and apoptosis. There has been significant progress in understanding the molecular mechanisms that mediate TNFa -induced cellular responses. Binding of TNFa to its two receptors, TNF-R1 and TNF-R2, results in the recruitment of signal transducers that activate at least three distinct effectors. Through complex signaling cascades and networks, these effectors lead to the activation of caspases and two transcription factors, AP-1 and NF-kappaB. Similar signaling mechanisms are likely to be used by other members of the TNF family. Lehmann et al . reported a highly significant correlation of TNFa and interferon (IFN)g production with activity and grade of gastritis, H. pylori density, epithelial cell apoptosis, and Fas/Fas-ligand expression. 14 T-cell lines and clones were all TCRab ( + ) and had the Th1 phenotype. Using serial histological sections, they demonstrated the in situ correlation of TNFa and IFNg with epithelial cell apoptosis, bacterial load, and histological severity of disease and emphasized the role of these cytokines in the pathophysiology of H. pyloriassociated diseases. An in vitro study using bone marrowderived mast cells indicated that H. pylori VacA cytotoxin directly bound to and had chemotactic activity to the mast cells that produce TN Fa , macrophageinflammatory protein-1 a , and other proinflammatory cytokines without causing degranulation. 15 Therefore, TNFa might be an important mediator in recruitment of mast cells, which have a pivotal role in gastric pathophysiology. In fact, polymorphism analyses on the TNFa gene indicate that the polymorphism could be a risk factor for gastroduodenal ulcers. 16 A study using knockout mice lacking TNF-R1 indicated that TNFR1-mediated TNF signals might support a systemic humoral immune response against H. pylori and that the gastric inflammatory response to H. pylori infection is independent of TNF-R1-mediated signals. 17