title: Inflammatory Cytokines Stimulate Bone Morphogenetic Protein-2 Expression and Release from Pancreatic Beta Cells.
abstract: The proinflammatory cytokines interleukin-1 beta (IL-1β) and interferon gamma (IFN-γ) play important roles in the progressive loss of beta-cell mass and function during development of both type 1 and type 2 diabetes. We have recently showed that bone morphogenetic protein (BMP)-2 and -4 are expressed in pancreatic islets and inhibit beta-cell growth and function. In this study, we describe that IL-1β and IFN-γ induce the expression of BMP-2 suggesting a possible role for BMP-2 in mediating the effects of IL-1β and IFN-γ on beta-cell apoptosis and dysfunction. IL-1β increased BMP-2 mRNA levels 6- and 3-fold in isolated islets of Langerhans from neonatal rat and human. Downstream target genes of the BMP pathway were also increased by cytokine treatment and could be reversed by neutralization of endogenous BMP activity. Nuclear factor kappa B- (NFκB) binding sites were identified in the rat BMP-2 promoter, and reporter assays verified the role of NFκB in cytokine-induced BMP-2 expression. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays confirmed NFκB binding to BMP-2 promoter upon IL-1β stimulation in beta cells. In conclusion, we suggest that NFκB stimulates BMP-2 mRNA expression in rat and human beta cells upon cytokine exposure.
authors: 1 Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen , Copenhagen N, Denmark .
authors: Adriana
authors: A
authors: Ibarra Urizar
authors: 1 Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen , Copenhagen N, Denmark .
authors: Josefine
authors: J
authors: Friberg
authors: 2 Department of Cellular and Molecular Medicine, University of Copenhagen , Copenhagen N, Denmark .
authors: Dan Ploug
authors: DP
authors: Christensen
authors: 1 Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen , Copenhagen N, Denmark .
authors: Gitte
authors: G
authors: Lund Christensen
authors: 1 Section of Cellular and Metabolic Research, Department of Biomedical Sciences, University of Copenhagen , Copenhagen N, Denmark .
authors: Nils
authors: N
authors: Billestrup
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D046509:Tissue Culture Techniques
chemical_list: C525720:Bmp2 protein, rat; D055396:Bone Morphogenetic Protein 2; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D007371:Interferon-gamma