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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 830-836
Copyright © 2000 by The Endocrine Society

Original Studies

Interferon-{gamma} Induces Interleukin-1 Converting Enzyme Expression in Pancreatic Islets by an Interferon Regulatory Factor-1-Dependent Mechanism1

Allan E. Karlsen, Dejan Pavlovic, Karin Nielsen, Jan Jensen, Henrik U. Andersen, Flemming Pociot, Thomas Mandrup-Poulsen, Décio L. Eizirik and Jørn Nerup

Steno Diabetes Center and Hagedorn Research Institute (A.E.K., K.N., J.J., H.U.A., F.P., T.M.-P., J.N.), 2820 Gentofte, Denmark; and Diabetes Research Center, Vrije Universiteit Brussel (D.P., D.L.E.), B-1090 Brussels, Belgium

Address correspondence and requests for reprints to: Dr. Allan E. Karlsen, Steno Diabetes Center, Niels Steensensvej 2, 2820 Gentofte, Denmark. E-mail: aek{at}novo.dk

Whereas nitric oxide (NO) production is associated with the toxic effect of cytokines on rodent pancreatic ß-cells, cytokine-induced apoptosis in human islets may occur independently of NO. The cysteine protease interleukin (IL)-1 converting enzyme (ICE) is a key proapoptotic caspase. Our aim was therefore to analyze the effect of cytokines on ICE expression in human, rat, and mouse islets and rat insulinoma cells.

ICE messenger RNA (mRNA) expression was highly up-regulated after 6-, 24-, and 72-h exposure of human islets to interferon (IFN){gamma}, tumor necrosis factor (TNF){alpha} + IFN{gamma} or IL-1ß + TNF{alpha} + IFN{gamma}, paralleled by increased iNOS (the inducible form of NO synthase) expression and NO production after exposure to the combined cytokines but not to IFN{gamma} or TNF{alpha} + IFN{gamma}. Cytokine-induced NO-independent ICE transcription was confirmed using iNOS inhibitors.

Exposure of rat and mouse islets, or rat insulinoma cells, for 24 h to IFN{gamma} alone or in combination with the two other cytokines also resulted in a highly significant ICE mRNA expression. ICE transcription was not inducible in islets from IFN regulatory factor-1 knock-out mice, suggesting a key-role of this transcription-factor in cytokine-mediated ICE expression in pancreatic islets.

In conclusion, cytokines and IFN{gamma} in particular increase ICE mRNA expression in pancreatic islet cells and ß-cell lines, independently of NO synthesis, suggesting that ICE up-regulation may be involved in cytokine-induced NO-independent apoptosis of human islets.




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