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-1beta 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 cytokine-induced 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.
Kim
Kyoung-Ah
KA
Department of Medicine, Dongguk University International Hospital,Dongguk University School of Medicine, Goyang, Korea.
Lee
Myung-Shik
MS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016207:Cytokines / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D007515:Islets of Langerhans / Q000166:cytology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology; D015854:Up-Regulation; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology
D016207:Cytokines; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D051636:X-Linked Inhibitor of Apoptosis Protein