Activation of the dual-leucine-zipper-bearing kinase and induction of beta-cell apoptosis by the immunosuppressive drug cyclosporin A

Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a beta-cell toxic effect has been described. However, its molecular mechanism remai...

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Bibliographic Details
Published in:Molecular pharmacology 2008-03, Vol.73 (3), p.652-659
Main Authors: Plaumann, Silke, Blume, Roland, Börchers, Svenja, Steinfelder, Hans Jürgen, Knepel, Willhart, Oetjen, Elke
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
bcl-X Protein - genetics
bcl-X Protein - metabolism
Calcineurin Inhibitors
Caspase 3 - metabolism
Cell Death - drug effects
Cell Line
Cell Survival - drug effects
Cyclosporine - pharmacology
DNA Fragmentation
Dose-Response Relationship, Drug
Enzyme Activation - drug effects
Formazans - metabolism
Immunohistochemistry
Immunosuppressive Agents - pharmacology
Inhibitory Concentration 50
Insulin-Secreting Cells - drug effects
Kinetics
MAP Kinase Kinase Kinases - analysis
MAP Kinase Kinase Kinases - metabolism
Mice
Statistics as Topic
Tacrolimus - pharmacology
Tetrazolium Salts - metabolism
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Summary:Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a beta-cell toxic effect has been described. However, its molecular mechanism remains unknown. In the present study, the effect of cyclosporin A and the dual leucine-zipper-bearing kinase (DLK) on beta-cell survival was investigated. Cyclosporin A decreased the viability of the insulin-producing pancreatic islet cell line HIT in a time- and concentration-dependent manner. Upon exposure to the immunosuppressant fragmentation of DNA, the activation of the effector caspase-3 and a decrease of full-length caspase-3 and Bcl(XL) were observed in HIT cells and in primary mature murine islets, respectively. Cyclosporin A and tacrolimus, both potent inhibitors of the calcium/calmodulin-dependent phosphatase calcineurin, stimulated the enzymatic activity of cellular DLK in an in vitro kinase assay. Immunocytochemistry revealed that the overexpression of DLK but not its kinase-dead mutant induced apoptosis and enhanced cyclosporin A-induced apoptosis to a higher extent than the drug alone. Moreover, in the presence of DLK, the effective concentration for cyclosporin A-caused apoptosis was similar to its known IC(50) value for the inhibition of calcineurin activity in beta cells. These data suggest that cyclosporin A through inhibition of calcineurin activates DLK, thereby leading to beta-cell apoptosis. This action may thus be a novel mechanism through which cyclosporin A precipitates post-transplant diabetes.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.107.040782