TY - JOUR
T1 - The transcription factor B-cell lymphoma (BCL)-6 modulates pancreatic {beta}-cell inflammatory responses
AU - Igoillo-Esteve, Mariana
AU - Gurzov, Esteban
AU - Eizirik, Decio
AU - Cnop, Miriam
PY - 2011
Y1 - 2011
N2 - Type 1 diabetes is a chronic autoimmune disease with a strong inflammatory component. We have previously shown that expression of the transcriptional repressor B-cell lymphoma (BCL)-6 is very low in pancreatic beta-cells, which may favor prolonged proinflammatory responses after exposure to the cytokines IL-1beta and interferon gamma. Here we investigated whether cytokine-induced inflammation and apoptosis can be prevented in beta-cells by BCL-6 expression using plasmid, prolactin, and adenoviral approaches. The induction of mild or abundant BCL-6 expression in beta-cells by prolactin or an adenoviral BCL-6 expression construct, respectively, reduced cytokine-induced inflammatory responses in a dose-dependent manner through inhibition of nuclear factor-kappaB activation. BCL-6 decreased Fas and inducible nitric oxide synthase expression and nitric oxide production, but it inhibited the expression of the antiapoptotic proteins Bcl-2 and JunB while increasing the expression of the proapoptotic death protein 5. The net result of these opposite effects was an augmentation of beta-cell apoptosis. In conclusion, BCL-6 expression tones down the unrestrained cytokine-induced proinflammatory response of beta-cells but it also favors gene networks leading to apoptosis. This suggests that cytokine-induced proinflammatory and proapoptotic signals can be dissociated in beta-cells. Further understanding of these pathways may open new possibilities to improve beta-cell survival in early type 1 diabetes or after transplantation.
AB - Type 1 diabetes is a chronic autoimmune disease with a strong inflammatory component. We have previously shown that expression of the transcriptional repressor B-cell lymphoma (BCL)-6 is very low in pancreatic beta-cells, which may favor prolonged proinflammatory responses after exposure to the cytokines IL-1beta and interferon gamma. Here we investigated whether cytokine-induced inflammation and apoptosis can be prevented in beta-cells by BCL-6 expression using plasmid, prolactin, and adenoviral approaches. The induction of mild or abundant BCL-6 expression in beta-cells by prolactin or an adenoviral BCL-6 expression construct, respectively, reduced cytokine-induced inflammatory responses in a dose-dependent manner through inhibition of nuclear factor-kappaB activation. BCL-6 decreased Fas and inducible nitric oxide synthase expression and nitric oxide production, but it inhibited the expression of the antiapoptotic proteins Bcl-2 and JunB while increasing the expression of the proapoptotic death protein 5. The net result of these opposite effects was an augmentation of beta-cell apoptosis. In conclusion, BCL-6 expression tones down the unrestrained cytokine-induced proinflammatory response of beta-cells but it also favors gene networks leading to apoptosis. This suggests that cytokine-induced proinflammatory and proapoptotic signals can be dissociated in beta-cells. Further understanding of these pathways may open new possibilities to improve beta-cell survival in early type 1 diabetes or after transplantation.
UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21190961
U2 - 10.1210/en.2010-0790
DO - 10.1210/en.2010-0790
M3 - Article
VL - 152
SP - 447
EP - 456
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 2
ER -