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Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells

Fernanda Ortis, Najib Naamane, Daisy Flamez (UGent) , Laurence Ladrière, Fabrice Moore, Daniel A Cunha, Maikel L Colli, Thomas Thykjaer, Kasper Thorsen, Torben F Ørntoft, et al.
(2010) DIABETES. 59(2). p.358-374
Author
Organization
Abstract
OBJECTIVE-Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cytokines interleukin (IL)-1 beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells. RESEARCH DESIGN AND METHODS-Fluorescence-activated cell sorter-purified rat a-cells were exposed to IL-1 beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h, and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis. RESULTS-Nearly 16,000 transcripts were detected as present in beta-cells, with temporal differences in the number of genes modulated by IL-1 beta + IFN gamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-a, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes. CONCLUSIONS-The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also shows that cytokines modify alternative splicing in beta-cells, opening a new avenue of research for the field.
Keywords
FACTOR-KAPPA-B, ENDOPLASMIC-RETICULUM STRESS, APOPTOSIS, INDUCTION, DEATH, TYPE-1, DIABETES-MELLITUS, INDUCED DYSFUNCTION, GENE-EXPRESSION, MESSENGER-RNA

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MLA
Ortis, Fernanda, et al. “Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells.” DIABETES, vol. 59, no. 2, 2010, pp. 358–74, doi:10.2337/db09-1159.
APA
Ortis, F., Naamane, N., Flamez, D., Ladrière, L., Moore, F., Cunha, D. A., … Eizirik, D. L. (2010). Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells. DIABETES, 59(2), 358–374. https://doi.org/10.2337/db09-1159
Chicago author-date
Ortis, Fernanda, Najib Naamane, Daisy Flamez, Laurence Ladrière, Fabrice Moore, Daniel A Cunha, Maikel L Colli, et al. 2010. “Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells.” DIABETES 59 (2): 358–74. https://doi.org/10.2337/db09-1159.
Chicago author-date (all authors)
Ortis, Fernanda, Najib Naamane, Daisy Flamez, Laurence Ladrière, Fabrice Moore, Daniel A Cunha, Maikel L Colli, Thomas Thykjaer, Kasper Thorsen, Torben F Ørntoft, and Decio L Eizirik. 2010. “Cytokines Interleukin-1β and Tumor Necrosis Factor-α Regulate Different Transcriptional and Alternative Splicing Networks in Primary β-Cells.” DIABETES 59 (2): 358–374. doi:10.2337/db09-1159.
Vancouver
1.
Ortis F, Naamane N, Flamez D, Ladrière L, Moore F, Cunha DA, et al. Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells. DIABETES. 2010;59(2):358–74.
IEEE
[1]
F. Ortis et al., “Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells,” DIABETES, vol. 59, no. 2, pp. 358–374, 2010.
@article{1072871,
  abstract     = {{OBJECTIVE-Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified by the cytokines interleukin (IL)-1 beta + interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha + IFN-gamma in primary rat beta-cells.
RESEARCH DESIGN AND METHODS-Fluorescence-activated cell sorter-purified rat a-cells were exposed to IL-1 beta + IFN-gamma or TNF-alpha + IFN-gamma for 6 or 24 h, and global gene expression was analyzed by microarray. Key results were confirmed by RT-PCR, and small-interfering RNAs were used to investigate the mechanistic role of novel and relevant transcription factors identified by pathway analysis.
RESULTS-Nearly 16,000 transcripts were detected as present in beta-cells, with temporal differences in the number of genes modulated by IL-1 beta + IFN gamma or TNF-alpha + IFN-gamma. These cytokine combinations induced differential expression of inflammatory response genes, which is related to differential induction of IFN regulatory factor-7. Both treatments decreased the expression of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-a, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine-induced changes in alternative splicing of >50% of the cytokine-modified genes.
CONCLUSIONS-The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also shows that cytokines modify alternative splicing in beta-cells, opening a new avenue of research for the field.}},
  author       = {{Ortis, Fernanda and Naamane, Najib and Flamez, Daisy and Ladrière, Laurence and Moore, Fabrice and Cunha, Daniel A and Colli, Maikel L and Thykjaer, Thomas and Thorsen, Kasper and Ørntoft, Torben F and Eizirik, Decio L}},
  issn         = {{0012-1797}},
  journal      = {{DIABETES}},
  keywords     = {{FACTOR-KAPPA-B,ENDOPLASMIC-RETICULUM STRESS,APOPTOSIS,INDUCTION,DEATH,TYPE-1,DIABETES-MELLITUS,INDUCED DYSFUNCTION,GENE-EXPRESSION,MESSENGER-RNA}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{358--374}},
  title        = {{Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells}},
  url          = {{http://doi.org/10.2337/db09-1159}},
  volume       = {{59}},
  year         = {{2010}},
}
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