TRAILing gastrointestinal pathogenesis (2003)

See article in J. Gastroenterol. Hepatol. 2003; 18: 763–770 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)-α.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. TNF-α 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 TNF-α-induced cellular responses. Binding of TNF-α 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 TNF-α and interferon (IFN)-γ 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 TCR-αβ(+) and had the Th1 phenotype. Using serial histological sections, they demonstrated the in situ correlation of TNF-α and IFN-γ with epithelial cell apoptosis, bacterial load, and histological severity of disease and emphasized the role of these cytokines in the pathophysiology of H. pylori-associated diseases. An in vitro study using bone marrow-derived mast cells indicated that H. pylori VacA cytotoxin directly bound to and had chemotactic activity to the mast cells that produce ΤΝF-α, macrophage-inflammatory protein-1α, and other proinflammatory cytokines without causing degranulation.15 Therefore, TNF-α might be an important mediator in recruitment of mast cells, which have a pivotal role in gastric pathophysiology. In fact, polymorphism analyses on the TNF-α gene indicate that the polymorphism could be a risk factor for gastroduodenal ulcers.16 A study using knockout mice lacking TNF-R1 indicated that TNF-R1-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 The Fas ligand (FasL) is a 40-kDa member of the TNF family. It was first reported in activated T lymphocytes and participates in cell-mediated cytotoxicity against virally infected or transformed cells. It is also present in the testis, the anterior chamber of the eye, the placenta and the brain,18 and contributes to the immune-privileged status of these organs by eliminating infiltrating lymphocytes. Its receptor, Fas (also known as Apo1 or CD95), is a type I transmembrane member of the TNF receptor super family, which, upon activation, signals apoptosis (death receptor, DR) in normal and transformed cells.18 Fas is expressed in myeloid and lymphoblastoid cells, fibroblasts, and several non-lymphoid tissues, such as the liver, ovary, lung and heart, and various carcinoma cell lines.18 Its cytoplasmic domain contains a 68-amino acid motif that is both necessary and sufficient for the induction of apoptosis. Upon cross-linking by FasL or the polyvalent antibodies, Fas recruits the adaptor molecule FADD (Fas-associating protein with a death domain), and then recruits the proenzyme form of caspase-8. The aggregation of Fas, FADD and caspase-8, and the Fas oligomerization brings several molecules of pro-caspase-8 into close proximity, resulting in the proteolytic autoactivation of caspase-8.19, 20 The resulting subunits p10 and p18 are released into the cytoplasm where they form an enzymatically active complex that triggers the downstream caspase cascade. FasL/Fas participates in the inflammatory destruction of target organs in several autoimmune disorders, such as Sjögren's syndrome, type I diabetes, ulcerative colitis, autoimmune hepatitis, experimental autoimmune encephalomyelitis, and uveoretinitis.18-21 It is suggested that PCD in gastric epithelium is mediated at least in part through Fas–FasL interactions in H. pylori disease pathogenesis.22 One study demonstrated that gastric T cells expressing FasL can induce PCD in gastric epithelial cells.23 Lymphocytes, however, also express Fas and can be directed to induce PCD. Jones et al. investigated the influence of H. pylori infection in mice deficient in the FasL (gld) and C57BL/6 mice.24 Both groups of mice had a similar degree of gastritis and the bacterial colonization was comparable in each group. Of the H. pylori-infected gld mice, 67% displayed atrophic changes in the gastric mucosa, compared with 37% of infected C57BL/6 mice. In addition, atrophic changes were more severe in H. pylori-infected gld mice. Splenocytes isolated from H. pylori-infected C57BL/6 mice had a twofold increase in the production of the Th1 cytokine IFN-γ in response to H. pylori antigens compared to controls. In contrast, there was a lack of detectable IFN-γ in gld mice infected with the bacterium. H. pylori-infected C57BL/6 mice had increased epithelial cell apoptosis compared with sham-infected C57BL/6 mice. These data demonstrate that mice with mutations in the FasL develop more severe premalignant mucosal changes in response to infection with H. pylori in association with both an impaired gastric epithelial cell apoptotic response and IFN production. Deregulation of the Fas pathway could be involved in the transition from gastritis to gastric cancers during H. pylori infection. In contrast, potent pro-apoptotic activity has been attributed to another member of the TNF family of ligands, TRAIL. TRAIL induces apoptosis by interacting with two cell-surface death receptors: DR4 (or TRAIL-R1) and DR5 (or TRAIL-R2).25 TRAIL is expressed in a wide range of normal fetal and adult tissues, suggesting the existence of a protective mechanism against its cytotoxicity in normal cells. This finding has been supported by observations that TRAIL could induce apoptosis in transformed and malignant cells, but not in normal cells.25 Three additional receptors for TRAIL that cannot transduce an apoptotic signal were also cloned: decoy receptor-1 (DcR1, also named TRAIL-R3 or TRID), DcR2 (TRAIL-R4 or TRUNDD), and osteoprotegerin.26 The expression of these decoy receptors was reported in non-neoplastic cells only and was proposed to be the reason for their resistance to TRAIL. Subsequent studies, however, revealed the presence of ‘decoy’ receptor mRNA and protein in cancer cells as well.27, 28 Untransformed hepatocytes, keratinocytes and prostatic epithelial cells were recently reported to be sensitive to TRAIL,29-31 a finding inconsistent with unconditional and selective anticancer activity of TRAIL. TRAIL and its receptors have a possible role in PCD in transformed and untransformed cells under certain circumstances, as has been suggested in TNF-α/TNF-receptors and FasL/Fas. In this issue, Koyama reports that non-neoplastic gastric mucosa expressed significant levels of TRAIL, DR4/DR5 and DcR2.18 Interestingly, both epithelial cells and lymphocytes express the ligand and the receptors. Although evidence is still lacking, these results suggest that mucosal epithelial cells and mucosal lymphocytes interact with each other using TRAIL and its receptors. Koyama's data are the first pieces of a new jigsaw puzzle of cell kinetics in mucosal epithelium and lymphocytes. Does H. pylori induce TRAIL and its receptors in gastric epithelium? Is there an association between TRAIL and other TNF-like ligands in the stomach? Is it true that gastric epithelium is resistant to TRAIL-related PCD? If so, what is the mechanism of resistance of normal cells to TRAIL? Does TRAIL regulate expansion of certain subpopulations of gastric lymphocytes such as CD8+CD11b– cells and CD4+CD62L– cells? We recently reported that TNF-α activates the invasive potential of immortalized intestinal epithelium with either v-src or TGF-α.32 Furthermore, another TNF-like ligand for the DR3 receptor and the TR6/DcR3 decoy receptor was recently discovered and is reported to have a role in T cell expansion.33 Does TRAIL have any functions other than inducing PCD? Many questions remain unanswered and wait to challenge gastroenterologists.