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Diabetes and Vascular Disease Research
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Dominance of cytokine- over FasL-induced impairment of the mitochondrial transmembrane potential ({Delta}{Psi}m) in the pancreatic β-cell line NIT-1

Petra Augstein

Institute of Diabetes "Gerhardt Katsch" Karlsburg e.V., Karlsburg, Germany.

Peter Heinke

Institute of Diabetes "Gerhardt Katsch" Karlsburg e.V., Karlsburg, Germany.

Eckhard Salzsieder

Institute of Diabetes "Gerhardt Katsch" Karlsburg e.V., Karlsburg, Germany.

Rita Grimm

Department of Physiology of the Ernst-Moritz-Arndt University of Greifswald, Karlsburg, Germany.

Jürgen Giebel

Department of Anatomy of the Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany.

Christel Salzsieder

Institute of Diabetes "Gerhardt Katsch" Karlsburg e.V., Karlsburg, Germany.

Leonard C Harrison

Autoimmunity and Transplantation Division, the Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.

Mitochondria of pancreatic β-cells are potential targets of intrinsic and extrinsic apoptotic pathways in the autoimmune pathogenesis of type 1 diabetes. We aimed to investigate whether cytokine- and FasLigand (FasL)-induced apoptosis is associated with impaired mitochondrial transmembrane potential ({Delta}{Psi}m) in the pancreatic β-cell line NIT-1. NIT-1 cells were exposed to the interleukin-1 β/interferon-{gamma} (IL-1 β/IFN-{gamma}) cytokine combination to induce apoptosis in vitro. Low concentrations of cytokines resulted in {Delta}{Psi}m impairment, and increasing concentrations had only a minor additional effect. Treatment with the inducible nitric oxide synthase (iNOS) inhibitor N{omega}-nitro-L-arginine methyl ester hydrochloride (L-NAME) prevented cytokine-mediated {Delta}{Psi}m impairment, implying that cytokines affect {Delta}{Psi}m via nitric oxide. The broad-spectrum caspase inhibitor Z-VAD(Ome)-FMK (ZVAD) revealed dichotomic actions. In the presence of ZVAD, cytokine-induced nitrite generation was increased but cell death and {Delta}{Psi}m impairment were reduced. {Delta}{Psi}m impairment was also reduced by inhibitors of caspases 1, 6 and 8. Induction of Fas by IL-1 β/IFN-{gamma} coupled with activation by Super-FasL augmented cytokine-induced cell death. We observed a clear dominance of cytokine- over FasL-induced effects on {Delta}{Psi}m.

Our findings show that IL-1 β/IFN-{gamma} cytokines have a strong effect to impair {Delta}{Psi}m and prime β-cells for apoptosis via the intrinsic pathway mediated by iNOS and caspases. Furthermore, at least in NIT-1 cells, the extrinsic FasL/Fas pathway has only a minor additive effect on cytokine-induced {Delta}{Psi}m impairment.

Key Words: β-cell line NIT-1 • cytokine-induced apoptosis • FasLigand-induced apoptosis • mitochondrial transmembrane potential • type 1 diabetes

References

Diabetes and Vascular Disease Research, Vol. 5, No. 3, 198-204 (2008)
DOI: 10.3132/dvdr.2008.032
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This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Augstein, P.
Right arrow Articles by Harrison, L. C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Augstein, P.
Right arrow Articles by Harrison, L. C
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*NITRIC OXIDE
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?