Inhibition of nuclear factor-κB activation in pancreatic ß-cells has a protective effect on allogeneic pancreatic islet graft survival.
PLoS One
; 8(2): e56924, 2013.
Article
em En
| MEDLINE
| ID: mdl-23437272
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-κB activation is involved in cytokine-mediated ß-cell apoptosis and regulates the expression of pro-inflammatory and chemokine genes. We therefore sought to explore the effects of ß-cell-specific inhibition of NF-κB activation as a means of cytoprotection in an allogeneic model of islet transplantation. To this end, we used islets isolated from the ToI-ß transgenic mouse, where NF-κB signalling can specifically and conditionally be inhibited in ß-cells by expressing an inducible and non-degradable form of IκBα regulated by the tet-on system. Our results show that ß-cell-specific blockade of NF-κB 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-κB 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transplante das Ilhotas Pancreáticas
/
NF-kappa B
/
Células Secretoras de Insulina
/
Sobrevivência de Enxerto
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Israel