Identification of Novel Cytokine-Induced Genes in Pancreatic β-Cells by High-Density Oligonucleotide Arrays

Cardozo, Alessandra K; Kruhøffer, Mogens; Leeman, Ruth; Ørntoft, Torben F.; Eizirik, Décio L.

doi:10.2337/diabetes.50.5.909

Cited by 230 publications

(325 citation statements)

References 89 publications

(74 reference statements)

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“…Recent evidence suggests that chemokines could play a role in the pathogenesis of Type 1 diabetes. FACS-purified rat beta cells exposed to IL-1β and IFN-γ or to double stranded RNA have increased mRNA expression for several cytokines and chemokines including MCP-1, IP-10, MIP-3α, fractalkine and IL-15 [8,9,47], and transgenic expression of MCP-1 in beta cells leads to insulitis [48]. These results were intriguing, and suggested that the highly differentiated beta cells would plified from the same sample (cytokine or chemokine copies/β-actin copies).…”

Section: Discussionmentioning

confidence: 99%

“…For measurements of cytokine or chemokine release by ELISA, human islets cells (10 5 ) were cultured for 72 h with or without recombinant human IL-1β (50 U/ml), recombinant human IFN-γ (1000 U/ml) and recombinant murine TNF-α (1000 U/ml, Innogenetics, Zwijnaarde, Belgium). The choice of cytokine and L-MA concentrations are based on our previous data [6,8,9]. All experimental procedures described in this and the sessions mentioned below were approved and carried out in accordance with the Ethics Committees of the Vrije Universiteit Brussel, Université Libre de Bruxelles, Katholieke Universiteit Leuven and the European Hospitals affiliated with the Eurotransplant Foundation (Leiden, The Netherlands) and β-Cell Transplant (Brussels, Belgium).…”

Section: Methodsmentioning

confidence: 99%

“…The primer sequences and their respective PCR fragment lengths for the human genes were as follows: hIL-15: F 5′-GA-TGGATGGCTGCTGGAAAC-3′, R 5′-GCATCTCCGGACTC-AAGTGA-3′ (390 bp); hIP-10: F 5′-CCACGTGTTGAGATC-ATTGC-3′, R 5′-ACATAGCACCTCAGTAGAGC-3′ (382 bp); hMIP-3α: F 5′-GTGCTGTACCAAGAGTTTGC-3′, R 5′-GAC-AAGTCCAGTGAGGCACA-3′ (420 bp); hFractalkine: F 5′-A-CGCACAGGCGAAAGCAGTA-3′, R 5′-TTCAGACGGAG-CATTCTCCT-3′ (340 bp); GAPDH: F 5′-CATGTTCGTC-ATGGGTGTGA-3′, R 5′-AGTGAGCTTCCCGTTCAGCT-3′ (300 bp). The rat primers for GAPDH, IL-15, IP-10, MIP-3α and fractalkine were as described [9]. The ethidium bromidestained agarose gels were photographed under UV-transillumination using a Kodak Digital Science DC 120 camera (Kodak, Rochester, N.Y., USA).…”

Section: Isolation and Transplantation Of Islets From Nod Micementioning

confidence: 99%

“…We have previously reported that rat and human islet cells, and islets isolated from pre-diabetic NOD mice, express the monocyte chemoattractant protein-1 (MCP-1) [7,8]. In subsequent experiments, based on microarray analysis, we observed that rat beta cells exposed to the cytokines IL-1β and IFN-γ have increased expression of mRNAs for the chemokines interferon inducible protein-10 (IP-10), macrophage inflammatory protein-3α (MIP-3α), fractalkine and the cytokine interleukin-15 (IL-15) [9]. Induction of several of these chemokines is regulated via activation of NF-κB [10].…”

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confidence: 99%

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IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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Aims/hypothesis. Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1β and IFN-γ have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3α, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation. Methods. FACS-purified rat beta cells and human islets were cultured with IL-1β, IFN-γ and/or TNF-α. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2-or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA.Results. Human islets and rat beta cells express IP-10, MIP-3α, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-γ, while the expression of MIP-3α is IL-1β-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3α protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3α expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1β, IFN-γ, fractalkine, IP-10, MCP-1 and MIP-3α mRNAs were observed in the grafts. Conclusion/interpretation. Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction. [Diabetologia (2003) 46:255-266] Keywords Type 1 diabetes mellitus, chemokines, IL-15, NOD mice, beta cells, interferon-γ, interleukin-1β, pancreatic islets, islet transplantation, insulitis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Isolation and Transplantation Of Islets From Nod Micementioning

confidence: 99%

mentioning

confidence: 99%

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IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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“…We addressed this hypothesis using the Akita diabetic mouse which has a mutation in the insulin 2 gene (Ins2) (Cys96Tyr), and is characterized by progressive hyperglycemia with reduced bcell mass but without insulitis or obesity. [86][87][88] This mutation disrupts a disulfide bond in proinsulin between the A and B chains, and is expected to induce a drastic conformational change of this molecule (Figure 4b). Mutant insulin is not secreted and is presumably degraded.…”

Section: Diabetesmentioning

confidence: 99%

Roles of CHOP/GADD153 in endoplasmic reticulum stress

2003

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Endoplasmic reticulum (ER) is the site of synthesis and folding of secretory proteins. Perturbations of ER homeostasis affect protein folding and cause ER stress. ER can sense the stress and respond to it through translational attenuation, upregulation of the genes for ER chaperones and related proteins, and degradation of unfolded proteins by a quality-control system. However, when the ER function is severely impaired, the organelle elicits apoptotic signals. ER stress has been implicated in a variety of common diseases such as diabetes, ischemia and neurodegenerative disorders. One of the components of the ER stress-mediated apoptosis pathway is C/EBP homologous protein (CHOP), also known as growth arrestand DNA damage-inducible gene 153 (GADD153). Here, we summarize the current understanding of the roles of CHOP/ GADD153 in ER stress-mediated apoptosis and in diseases including diabetes, brain ischemia and neurodegenerative disease.

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Development and Life Cycle of a β‐Cell

Serup¹,

Nielsen

2003

International Textbook of Diabetes Mellitus

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The understanding of the molecular biology of the pancreas β‐cell began 25 years ago with the cloning of the insulin cDNA, followed by the determination of the genomic organization and the identification of multiple cis ‐ and trans ‐acting elements in the 5′‐flanking region. The developmental biology of the pancreas started earlier but was put on hold until the molecular biological technology allowed approaching the questions raised some 30 years ago. A major breakthrough happened 8 years ago when disruption of the gene for an insulin gene transcription factor was found to ablate the development of the pancreas. This has greatly stimulated the search for new transcription factors and their regulation by growth and differentiation factors in order to understand the basal molecular mechanisms involved in the formation of the pancreas β‐cell and the perspectives for prevention, treatment, and cure of diabetes. The maintenance of an appropriate β‐cell mass depends on neogenesis from progenitor cells, proliferation of existing β‐cells, and β‐cell death. The balance between these processes is regulated by a complex interaction of metabolites, hormones, and growth factors. Under normal conditions there appears to be a close correspondence between insulin demand and the functional β‐cell mass. The function of the β‐cell is not only under acute regulation by nutrients following a meal but is also subject to regulation by chronic changes in the insulin demand as in pregnancy or obesity, which result in adjustment of the β‐cell number.

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Identification of Novel Cytokine-Induced Genes in Pancreatic β-Cells by High-Density Oligonucleotide Arrays

Cited by 230 publications

References 89 publications

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

Roles of CHOP/GADD153 in endoplasmic reticulum stress

Development and Life Cycle of a β‐Cell

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