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Updated: Aug 10, 2026
Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
Published on: December 27, 2016
Expression and function of death receptors and their natural ligands in the intestine
1Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
Abstract:
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.
Insights
The tumor necrosis factor receptor (TNFR) family, including CD95 and TRAIL, mediates apoptosis. While CD95 may impact inflammatory bowel diseases, TRAIL shows potential as an anticancer therapeutic agent due to tumor cell sensitivity.
Area of Science:
- Cellular Biology
- Immunology
- Molecular Biology
Background:
- The tumor necrosis factor receptor (TNFR) superfamily comprises transmembrane proteins, some possessing a "death domain" crucial for initiating apoptosis.
- Apoptosis, or programmed cell death, is triggered by receptor trimerization upon binding of natural ligands from the TNF family.
- CD95 (APO-1/Fas) is a well-characterized TNFR member expressed on colonic epithelial cells, though its precise role in gut physiology is debated.
Purpose of the Study:
- To explore the role of the CD95/CD95L system in intestinal epithelium regeneration and inflammatory bowel diseases.
- To investigate the resistance of colon carcinoma cell lines to CD95-induced apoptosis and the concept of "immunoprivileged sites."
- To examine the potential of TRAIL (TNF-related apoptosis-inducing ligand) and its receptors as anticancer therapeutics.
Main Methods:
- Analysis of CD95 expression in colonic epithelial cells.
- Investigation of CD95L expression in colon carcinoma cell lines.
- Characterization of TRAIL receptors (TRAIL-R1-4) and their apoptotic functions.
Main Results:
- CD95 is expressed on colonic epithelial cells, potentially involved in inflammatory bowel diseases but not physiologic regeneration.
- Colon carcinoma cells often resist CD95-induced apoptosis and may express CD95L, creating "immunoprivileged sites."
- TRAIL induces apoptosis in many tumor cell lines in vitro, while normal cells show resistance.
Conclusions:
- The CD95/CD95L system may contribute to inflammatory bowel disease pathogenesis and tumor immune evasion.
- TRAIL and its death domain-bearing receptors (TRAIL-R1/2) represent a promising therapeutic avenue for cancer treatment.
- Further research is warranted to fully elucidate the roles of TNFR superfamily members in gut health and disease.
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