title: The transcription factor B-cell lymphoma (BCL)-6 modulates pancreatic {beta}-cell inflammatory responses.
abstract: 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 β-cells, which may favor prolonged proinflammatory responses after exposure to the cytokines IL-1β and interferon γ. Here we investigated whether cytokine-induced inflammation and apoptosis can be prevented in β-cells by BCL-6 expression using plasmid, prolactin, and adenoviral approaches. The induction of mild or abundant BCL-6 expression in β-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-κB 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 β-cell apoptosis. In conclusion, BCL-6 expression tones down the unrestrained cytokine-induced proinflammatory response of β-cells but it also favors gene networks leading to apoptosis. This suggests that cytokine-induced proinflammatory and proapoptotic signals can be dissociated in β-cells. Further understanding of these pathways may open new possibilities to improve β-cell survival in early type 1 diabetes or after transplantation.
authors.affiliation: Laboratory of Experimental Medicine, Erasmus Hospital, Universite´ Libre de Bruxelles, 1070 Brussels, Belgium.
authors.forename: Mariana
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Miriam
authors.initials: M
authors.lastname: Cnop
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005576:Colforsin / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D000077270:Exenatide; D005455:Fluorescent Antibody Technique; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011388:Prolactin / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014688:Venoms / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D010455:Peptides; D051560:Proto-Oncogene Proteins c-bcl-6; D014688:Venoms; D019014:fas Receptor; D005576:Colforsin; D011388:Prolactin; D000077270:Exenatide; D052247:Nitric Oxide Synthase Type II