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TNF-related apoptosis-inducing ligand death pathway-mediated human beta-cell destruction.
Diabetologia. 2002 Dec; 45(12):1678-88.D

Abstract

AIMS/HYPOTHESIS

The aim of this study is to investigate whether apoptosis in human beta cells can be related to the induction of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway.

METHODS

We examined the expression of TRAIL and TRAIL receptors in two human pancreatic beta-cell lines and in human primary islet cells using RT-PCR assays and flow cytometric analyses and tested TRAIL-mediated beta-cell destruction in (51)Cr release cytotoxicity assays, Annexin-V and APO-DIREC assays.

RESULTS

Most of the human beta cells express TRAIL receptors-R1, -R2, -R3, -R4 and/or TRAIL. TRAIL induced much stronger cytotoxicity and apoptosis to beta-cell lines CM and HP62 than did FasL, TNF-alpha, LTalpha1beta2, LTalpha2beta1, LIGHT, and IFN-gamma. The cytotoxicity and apoptosis induced by TRAIL to beta-cell lines CM were inhibited competitively by soluble TRAIL receptors, R1, R2, R3 or R4. Treatment of these beta cells with antibodies against TRAIL receptors was able to block the cytotoxicity of TRAIL to these cells. Beta-cell antigen-specific CTL (CD4(+) and CD8(+)) clones express TRAIL, suggesting that these cells are potential sources of TRAIL-inducing beta-cell destruction. Normal primary islet cells from most donors are resistant to the cytotoxicity mediated by TRAIL. However, treatment with an inhibitor of protein synthesis (cycloheximide) or with an enzyme (PI-PLC) that can remove TRAIL-R3 from the islet-cell membrane was able to increase the susceptibility of TRAIL-resistant primary islet cells to the TRAIL death pathway.

CONCLUSION/INTERPRETATION

The TRAIL death pathway is present and can function in human islet beta cells, but unidentified inhibitors of the TRAIL death pathway are present in normal islet cells.

Authors+Show Affiliations

Department of Pediatrics, University of British Columbia, Canada. daweiou@interchange.ubc.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12488957

Citation

Ou, D, et al. "TNF-related Apoptosis-inducing Ligand Death Pathway-mediated Human Beta-cell Destruction." Diabetologia, vol. 45, no. 12, 2002, pp. 1678-88.
Ou D, Metzger DL, Wang X, et al. TNF-related apoptosis-inducing ligand death pathway-mediated human beta-cell destruction. Diabetologia. 2002;45(12):1678-88.
Ou, D., Metzger, D. L., Wang, X., Huang, J., Pozzilli, P., & Tingle, A. J. (2002). TNF-related apoptosis-inducing ligand death pathway-mediated human beta-cell destruction. Diabetologia, 45(12), 1678-88.
Ou D, et al. TNF-related Apoptosis-inducing Ligand Death Pathway-mediated Human Beta-cell Destruction. Diabetologia. 2002;45(12):1678-88. PubMed PMID: 12488957.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TNF-related apoptosis-inducing ligand death pathway-mediated human beta-cell destruction. AU - Ou,D, AU - Metzger,D L, AU - Wang,X, AU - Huang,J, AU - Pozzilli,P, AU - Tingle,A J, Y1 - 2002/10/23/ PY - 2002/03/21/received PY - 2002/06/24/revised PY - 2002/12/19/pubmed PY - 2003/7/3/medline PY - 2002/12/19/entrez SP - 1678 EP - 88 JF - Diabetologia JO - Diabetologia VL - 45 IS - 12 N2 - AIMS/HYPOTHESIS: The aim of this study is to investigate whether apoptosis in human beta cells can be related to the induction of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. METHODS: We examined the expression of TRAIL and TRAIL receptors in two human pancreatic beta-cell lines and in human primary islet cells using RT-PCR assays and flow cytometric analyses and tested TRAIL-mediated beta-cell destruction in (51)Cr release cytotoxicity assays, Annexin-V and APO-DIREC assays. RESULTS: Most of the human beta cells express TRAIL receptors-R1, -R2, -R3, -R4 and/or TRAIL. TRAIL induced much stronger cytotoxicity and apoptosis to beta-cell lines CM and HP62 than did FasL, TNF-alpha, LTalpha1beta2, LTalpha2beta1, LIGHT, and IFN-gamma. The cytotoxicity and apoptosis induced by TRAIL to beta-cell lines CM were inhibited competitively by soluble TRAIL receptors, R1, R2, R3 or R4. Treatment of these beta cells with antibodies against TRAIL receptors was able to block the cytotoxicity of TRAIL to these cells. Beta-cell antigen-specific CTL (CD4(+) and CD8(+)) clones express TRAIL, suggesting that these cells are potential sources of TRAIL-inducing beta-cell destruction. Normal primary islet cells from most donors are resistant to the cytotoxicity mediated by TRAIL. However, treatment with an inhibitor of protein synthesis (cycloheximide) or with an enzyme (PI-PLC) that can remove TRAIL-R3 from the islet-cell membrane was able to increase the susceptibility of TRAIL-resistant primary islet cells to the TRAIL death pathway. CONCLUSION/INTERPRETATION: The TRAIL death pathway is present and can function in human islet beta cells, but unidentified inhibitors of the TRAIL death pathway are present in normal islet cells. SN - 0012-186X UR - https://www.unboundmedicine.com/medline/citation/12488957/TNF_related_apoptosis_inducing_ligand_death_pathway_mediated_human_beta_cell_destruction_ L2 - https://doi.org/10.1007/s00125-002-0926-2 DB - PRIME DP - Unbound Medicine ER -