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Published on: August 2, 2021
Tissue distribution of the death ligand TRAIL and its receptors
Diana C Spierings1, Elisabeth G de Vries, Edo Vellenga
1Department of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands.
Abstract:
Recombinant human (rh) TNF-related apoptosis-inducing ligand (TRAIL) harbors potential as an anticancer agent. RhTRAIL induces apoptosis via the TRAIL receptors TRAIL-R1 and TRAIL-R2 in tumors and is non-toxic to nonhuman primates. Because limited data are available about TRAIL receptor distribution, we performed an immunohistochemical (IHC) analysis of the expression of TRAIL-R1, TRAIL-R2, the anti-apoptotic TRAIL receptor TRAIL-R3, and TRAIL in normal human and chimpanzee tissues. In humans, hepatocytes stained positive for TRAIL and TRAIL receptors and bile duct epithelium for TRAIL, TRAIL-R1, and TRAIL-R3. In brains, neurons expressed TRAIL-R1, TRAIL-R2, TRAIL-R3 but no TRAIL. In kidneys, TRAIL-R3 was negative, tubuli contorti expressed TRAIL-R1, TRAIL-R2, and TRAIL, and cells in Henle's loop expressed only TRAIL-R2. Heart myocytes showed positivity for all proteins studied. In colon, TRAIL-R1, TRAIL-R2, and TRAIL were present. Germ and Leydig cells were positive for all proteins studied. Endothelium in liver, heart, kidney, and testis lacked TRAIL-R1 and TRAIL-R2. In alveolar septa and bronchial epithelium TRAIL-R2 was expressed, brain vascular endothelium expressed TRAIL-R2 and TRAIL-R3, and in heart vascular endothelium only TRAIL-R3 was present. Only a few differences were observed between human and chimpanzee liver, brain, and kidney. In contrast to human, chimpanzee bile duct epithelium lacked TRAIL, TRAIL-R1, and TRAIL-R3, lung and colon showed no TRAIL or its receptors, TRAIL-R3 was absent in germ and Leydig cells, and vascular endothelium showed only TRAIL-R2 expression in the brain. In conclusion, comparable expression of TRAIL and TRAIL receptors was observed in human and chimpanzee tissues. Lack of liver toxicity in chimpanzees after rhTRAIL administration despite TRAIL-R1 and TRAIL-R2 expression is reassuring for rhTRAIL application in humans.
Insights
Recombinant human TRAIL (TNF-related apoptosis-inducing ligand) shows anticancer promise. Immunohistochemical analysis revealed comparable TRAIL and TRAIL receptor expression in human and chimpanzee tissues, supporting its potential therapeutic use.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Recombinant human TRAIL (rhTRAIL) is a potential anticancer agent that induces apoptosis via TRAIL-R1 and TRAIL-R2.
- Previous studies indicate rhTRAIL is non-toxic to nonhuman primates, but data on TRAIL receptor distribution are limited.
Purpose of the Study:
- To investigate the expression patterns of TRAIL, TRAIL-R1, TRAIL-R2, and TRAIL-R3 in normal human and chimpanzee tissues.
- To assess the implications of TRAIL receptor distribution for the safety and efficacy of rhTRAIL as an anticancer therapy.
Main Methods:
- Immunohistochemical (IHC) analysis was employed to detect TRAIL and its receptors (TRAIL-R1, TRAIL-R2, TRAIL-R3).
- Tissues examined included liver, brain, kidney, heart, colon, lungs, and reproductive organs from both humans and chimpanzees.
Main Results:
- TRAIL and its receptors were expressed in various human tissues, including hepatocytes, neurons, myocytes, and colon cells.
- Significant differences in TRAIL and receptor expression were noted between human and chimpanzee tissues, particularly in bile duct epithelium and colon.
- Despite TRAIL-R1 and TRAIL-R2 expression in chimpanzee liver, no liver toxicity was observed after rhTRAIL administration.
Conclusions:
- Comparable expression of TRAIL and its receptors was observed in human and chimpanzee tissues, suggesting conserved biological roles.
- The lack of liver toxicity in chimpanzees, despite receptor expression, is reassuring for the clinical application of rhTRAIL in humans.
- This study provides crucial data on TRAIL receptor distribution, supporting the further development of rhTRAIL-based cancer therapies.
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