Specific expression of Bax-omega in pancreatic beta-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-omega (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-alpha. No apoptosis or down-regulation of Bcl-2 and Bax-omega 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-omega, and apoptosis, occurred within 24 h. Primary rat beta-cells exhibited a higher expression of Bax-omega than MIN6 cells or than other rat cell types. These data suggest that suppression of the antiapoptotic proteins Bcl-2 and Bax-omega mediates cytokine-induced apoptosis of beta-cells. The beta-cell-specific expression of Bax-omega makes this protein a possible effector in the protection of this cell type against apoptosis.