Inhibition of Nuclear Factor-κB Activation in Pancreatic β-Cells Has a Protective Effect on Allogeneic Pancreatic Islet Graft Survival

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Abstract

Pancreatic islet transplantation, a treatment for type 1 diabetes, has met significant challenges, as a substantial fraction of the islet mass fails to engraft, partly due to death by apoptosis in the peri- and post-transplantation periods. Previous evidence has suggested that NF-kappaB activation is involved in cytokine-mediated beta-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of beta-cell-specific inhibition of NF-kappaB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-beta transgenic mouse, where NF-kappaB signalling can specifically and conditionally be inhibited in beta-cells by expressing an inducible and non-degradable form of IkappaBalpha regulated by the tet-on system. Our results show that beta-cell-specific blockade of NF-kappaB led to a prolonged islet graft survival, with a relative higher preservation of the engrafted endocrine tissue and reduced inflammation. Importantly, a longer delay in allograft rejection was achieved when mice were systemically treated with the proteasome inhibitor, Bortezomib. Our findings emphasize the contribution of NF-kappaB activation in the allograft rejection process, and suggest an involvement of the CXCL10/IP-10 chemokine. Furthermore, we suggest a potential, readily available therapeutic agent that may temper this process.

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Eldor, R., Abel, R., Sever, D., Sadoun, G., Peled, A., Sionov, R., & Melloul, D. (2013). Inhibition of Nuclear Factor-κB Activation in Pancreatic β-Cells Has a Protective Effect on Allogeneic Pancreatic Islet Graft Survival. PLoS ONE, 8(2). https://doi.org/10.1371/journal.pone.0056924

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