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Specific Expression of Bax- in Pancreatic ß-Cells Is Down-Regulated by Cytokines before the Onset of Apoptosis

Diabetes Research Center, Vrije Universiteit Brussel, B-1090 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. Mark Van de Casteele, Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium. E-mail: mvdcaste{at}vub.ac.be

Cytokines have been implicated in the process of pancreatic ß-cell destruction that leads to type 1 diabetes. This study investigates the ß-cell expression of pro- and antiapoptotic proteins from the Bcl-2 family and their variation during cytokine-mediated apoptosis. Exposure of rat ß-cells to the combination of IL-1ß plus interferon- causes a time-dependent increase in apoptotic cells starting after 3 d (<10% on d 3 and 28 ± 2% on d 7). This effect was preceded by a marked down-regulation of two antiapoptotic proteins, Bcl-2 and Bax- (respectively reduced by 60% and 80% after 3 d), whereas no changes occurred in the expression of Bcl-x_L and the proapoptotic protein Bax-. No apoptosis or down-regulation of Bcl-2 and Bax- proteins was observed with individual cytokines or in the presence of N-methyl-L-arginine, an inhibitor of nitric oxide synthase. The lowered Bcl-2 protein content was associated with a decrease in Bcl-2 mRNA, which was initiated after 24 h of exposure. In MIN6 cells, the cytokine-induced suppression of Bcl-2- and Bax-, and apoptosis, occurred within 24 h. Primary rat ß-cells exhibited a higher expression of Bax- than MIN6 cells or than other rat cell types. These data suggest that suppression of the antiapoptotic proteins Bcl-2 and Bax- mediates cytokine-induced apoptosis of ß-cells. The ß-cell-specific expression of Bax- makes this protein a possible effector in the protection of this cell type against apoptosis.

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