Specific expression of Bax-ω in pancreatic β-cells is down-regulated by cytokines before the onset of apoptosis

Cytokines have been implicated in the process of pancreatic beta-cell destruction that leads to type 1 diabetes. This study investigates the beta-cell expression of pro- and antiapoptotic proteins from the Bcl-2 family and their variation during cytokine-mediated apoptosis. Exposure of rat beta-cells to the combination of IL-1beta plus interferon-gamma 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-ω (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-α. No apoptosis or down-regulation of Bcl-2 and Bax-ω 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-ω, and apoptosis, occurred within 24 h. Primary rat β-cells exhibited a higher expression of Bax-ω than MIN6 cells or than other rat cell types. These data suggest that suppression of the antiapoptotic proteins Bcl-2 and Bax-ω mediates cytokine-induced apoptosis of β-cells. The β-cell-specific expression of Bax-ω makes this protein a possible effector in the protection of this cell type against apoptosis.