The transcription factor B-cell lymphoma (BCL)-6 modulates pancreatic {beta}-cell inflammatory responses

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.