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and tumour necrosis factor-
-induced apoptosis independent of nitric oxide production
Department of Medical Biochemistry and Genetics, University of Copenhagen, Panum Institute, Blegdamsvej 3, DK 2200 Copenhagen N, Denmark
1 Pharmacology Research 4, Novo Nordisk A/S, Novo Nordisk Park F6.2.13, DK 2760 Måløv, Denmark
2 Steno Diabetes Center, Niels Steensensvej 2, DK 2820 Gentofte, Denmark
(Requests for offprints should be addressed to J Jensen; Email: jj{at}imbg.ku.dk)
The proinflammatory cytokines interleukin-1ß (IL-1ß), interferon-
(IFN-) and tumour necrosis factor-
(TNF-) are toxic to pancreatic ß-cells and are implicated in the pathogenesis of type 1 diabetes. We have previously found that GH and prolactin (PRL) stimulate both proliferation and insulin production in pancreatic ß-cells and rat insulin-producing INS-1 cells. Here we report that human (h) GH can prevent the apoptotic effects of IL-1ß, IFN- and TNF- in INS-1 and INS-1E cells. Using adenovirus-mediated gene transfer, we found that the anti-apoptotic effect of hGH is abrogated by expression of a dominant negative signal transducer and activator of transcription (STAT5) mutant in INS-1E cells. hGH and the cytotoxic cytokines was found to additively increase suppressor of cytokine signalling-3 mRNA expression after 4 h of exposure. In order to identify possible targets for the STAT5-mediated protection of INS-1E cells, we studied the effect of hGH on activation of the transcription factors STAT1 and nuclear factor-
B (NF-B) by IFN- and IL-1ß+TNF- respectively. Gel retardation experiments showed that hGH affects neither IFN-+ TNF--induced STAT1 DNA binding nor IL-1ß and IFN-+TNF--induced NFB DNA binding. The lack of influence of hGH on cytokine-mediated activation of STAT1 and NFB is in accordance with the finding that hGH had only a minor effect on cytokine-induced inducible nitric oxide synthase (iNOS) gene expression and in fact augmented the IL-1ß-stimulated nitric oxide production. As the anti-apoptotic Bcl-xL gene has been shown to harbour a STAT5-binding element we measured the expression of Bcl-xL as well as the pro-apoptotic Bax. We found that hGH increased the Bcl-xL/Bax ratio both in the absence and in the presence of cytotoxic cytokines. In conclusion, these results suggested that GH and PRL protect ß-cells against cytotoxic cytokines via STAT5-dependent mechanisms distal to iNOS activation possibly at the level of Bcl-xL.
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