Expression and function of death receptors and their natural ligands in the intestine.

The tumor necrosis factor receptor (TNFR) family is a still-growing group of homologous transmembrane proteins, some of which bear an intracellular "death domain" and are able to directly mediate apoptosis. Apoptosis is induced upon trimerization of the receptors by their natural ligands' constituting the complementary TNF family. The best-characterized apoptosis-mediating TNFR family member is CD95 (APO-1/Fas). CD95 is functionally expressed on the basolateral surface of colonic epithelial cells regardless of their position along the crypt axis. The biological significance of this CD95 expression in the gut, however, is still under discussion. Although it is unlikely that the CD95/CD95L system is involved in the physiologic regeneration of the intestinal epithelium, this system may play an important role in the pathogenesis of inflammatory bowel diseases. In contrast to the normal epithelium, colon carcinoma cell lines are mostly resistant to CD95-induced apoptosis. The detection of CD95L expression in colon carcinoma cell lines has led to the concept of carcinomas as "immunoprivileged sites," where invading immune cells are killed by CD95L-expressing tumor cells. A more recently described member of the TNF family is TRAIL, which is also able to induce apoptosis. As yet, four TRAIL receptors have been cloned, two of which (TRAIL-R1 and 2) bear a death domain and mediate apoptosis, whereas two others (TRAIL-R3 and 4) lack (functional) death domains and are supposed to act as decoy receptors. Because many tumor cell lines in vitro are sensitive to TRAIL-induced apoptosis while their normal counterparts are not, TRAIL is currently under discussion as a possible anticancer therapeutic agent.