Recent progress in research on beta-cell apoptosis by cytokines

Pancreatic beta-cell apoptosis plays a critical role in the pathogenesis of type 1 diabetes mellitus. As death effector molecules, perforin, Fas ligand, tumor necrosis factor (TNF)-alpha, Interleukin (IL)-1, interferon (IFN)-gamma, and nitric oxide have been claimed. Recently, combinations or synergisms between IFN-gamma and TNF-alpha or IL-1β are being revisited as the death effectors, and signal transduction of such synergisms has been explored to find molecular mechanism of beta-cell death. Among the regulators of apoptosis, nuclear factor-kappaB (NF-kappaB) has emerged as a master switch of cytokineinduced beta-cell dysfunction and death. By employing TNF-alpha/IFN-gamma synergism model which causes beta-cell apoptosis, we found that the antiapoptotic X-linked inhibitor of apoptosis (XIAP) molecule is upregulated by NF-kappaB in response to TNF-alpha and XIAP induction was inhibited by IFN-gamma-induced signal transducer and activator of transcription-1 (STAT1) activation, which explains the death of beta-cells by TNF-alpha/IFN-gamma synergism.