Overexpression of the nuclear factor-κB subunit c-Rel protects against human islet cell death in vitro

Mokhtari D, Barbu A, Mehmeti I, Vercamer C, Welsh N. Overexpression of the nuclear factor-kappa B subunit c-Rel protects against human islet cell death in vitro. Am J Physiol Endocrinol Metab 297: E1067-E1077, 2009. First published August 25, 2009; doi: 10.1152/ajpendo.00212.2009.-The transcription factor nuclear factor (NF)-kappa B is known to modulate rates of apoptosis and may therefore play a role in the increased beta-cell death that occurs in type 1 and type 2 diabetes. The aim of the present investigation was to study the expression of NF-kappa B subunits in human islet cells and whether overexpression of the NF-kappa B subunit c-Rel affects islet cell survival. We detected expression of p65, Rel-B, p50, p105, p52, and the ribosomal protein S3 (rpS3) in human islet cells. Among these, only p65 and rpS3 were translocated from the cytosolic to the nuclear fraction in response to cytokines. Interestingly, rpS3 participated in p65 binding to the kappa B-element in gel shift analysis experiments. We observed cytoplasmic c-Rel expression in vivo in 6J mice, and signs of nuclear translocation in beta-cells of infiltrated nonobese diabetic islets. Human islet cells were also dispersed by trypsin treatment and transduced with a c-Rel adenoviral vector. This resulted in increased expression of c-Rel and inhibitory factor kappa B, increased kappa B-binding activity, and augmented protein levels of Bcl-X-L, c-IAP2, and heat shock protein 72. c-Rel expression in human islet cells protected against cytokine-induced caspase 3 activation and cell death. c-Rel protected also against streptozotocin- and H2O2-induced cell death, in both intact rat islets and human islet cells. We conclude that rpS3 participates in NF-kappa B signaling and that a genetic increase in the activity of the NF-kappa B subunit c-Rel results in protection against cell death in human islets.