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Inhibition of Protein Kinase C Protects Rat INS-1 Cells Against Interleukin-1ß and Streptozotocin-Induced Apoptosis

From the Garvan Institute of Medical Research, St. Vincents Hospital, Darlinghurst, Sydney, Australia

Exposure of pancreatic ß-cells to cytokines, such as interleukin-1ß (IL-1ß), is thought to contribute to the ß-cell apoptosis that underlies the onset of type 1 diabetes. One important event triggered by IL-1ß is induction of nitric oxide synthase (iNOS), an enzyme that catalyzes intracellular generation of the cytotoxic free radical NO. We recently described a novel requirement for the protein kinase C (PKC) isozyme PKC in this process. Our current aim, therefore, was to assess whether PKC also plays a role in ß-cell apoptosis. As assessed by either annexin V staining or DNA fragmentation, IL-1ß caused INS-1 cells to undergo apoptosis. This was completely blocked by adenoviral overexpression of a dominant-negative, kinase-dead (KD) PKC mutant. The corresponding PKC virus was without effect. However, apoptosis caused by the cytotoxic agent streptozotocin (STZ), which acts independent of iNOS, was also inhibited by overexpression of PKCKD. STZ was additionally shown to activate the proteolytic enzyme caspase-3, a key biochemical effector of end-stage apoptosis. Moreover, STZ caused a caspase-dependent cleavage of PKC, thereby releasing a COOH-terminal fragment corresponding to the kinase catalytic domain. Thus, proteolytic activation of PKC seems to be important in the distal apoptotic pathway induced by STZ. That IL-1ß also activated caspase-3 and promoted PKC cleavage suggests that this distal pathway also contributes in the apoptotic response to the cytokine. These data therefore support a dual role for PKC in IL-1ß-mediated cell death: it is required for efficient NO generation through regulation of iNOS levels but also contributes to apoptotic pathways downstream of caspase activation.

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