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  • Title: Identification of interleukin 1-induced apoptosis in rat islets using in situ specific labelling of fragmented DNA.
    Author: Dunger A, Augstein P, Schmidt S, Fischer U.
    Journal: J Autoimmun; 1996 Jun; 9(3):309-13. PubMed ID: 8816965.
    Abstract:
    To study the ability of interleukin 1-beta (IL-1) to induce apoptosis in the endocrine pancreas, rat islets of Langerhans obtained from 14-day-old BB.1A rats were exposed to 25 U/ml IL-1 for 40 h. In order to prove the role of nitric oxide (NO) in this process islets were exposed either to 1 mmol/l N-nitro-L-arginine methylester (NAME) or to 25 mmol/l nicotinamide (NA) or to a combination of NA or NAME with IL-1. In dispersed cells oligonucleosomes, resulting from cleavage of nuclear DNA due to apoptosis, were identified by enzymatic labelling the free 3'-OH-DNA ends with fluorescein-dUTP and quantified by means of flow cytometry. After exposure to IL-1, the islets were characterized by elevated basal (in response to 2 mmol/l glucose) insulin release while glucose-stimulated (20 mmol/l glucose) insulin secretion was nearly completely abolished. In contrast, glucose-stimulated insulin secretion was well preserved in NAME-exposed islets, but was markedly inhibited after NA treatment. Accordingly, only the IL-1-induced inhibition of glucose-stimulated insulin secretion was significantly restored in the presence of NAME but was reinforced by NA. IL-1 exposure resulted in a significant increase in the percentage of apoptotic cells (untreated controls 3.8 +/- 0.5% IL-1 18.8 +/- 1.8%, P < 0.01). This effect was significantly reduced in the presence of NA and NAME. Nitrite production which was assayed as an equivalent of NO generation of islets was highest under the influence of IL-1 (16.48 +/- 1.40 versus 2.89 +/- 0.37 pmol/islet for control islets) which was correlated with the percentage of apoptotic cells. IL-1-stimulated nitrite production was reduced to 9.25 +/- 0.48 and 3.41 +/- 0.36 pmol/islet in the presence of NA or NAME, respectively. The results demonstrate the potency of IL-1 to induce apoptosis in rat islets. Since inhibition of NO production was always paralleled by a reduced ability of IL-1 to induce programmed cell death, this radical appears to be involved in this process. Remarkably, the near-complete prevention of NO generation as demonstrated under the influence of NAME was able to prevent the IL-1-induced deterioration of glucose-stimulated insulin secretion in parallel to the prevention of apoptosis-related appearance of DNA double-strand breaks. It is concluded that the elimination of damaged beta cells due to IL-1 exposure is partly achieved by induction of apoptosis.
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