Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans

Spinas, Giatgen A.; Hansen, Birgit Sehested; Linde, Susanne; Kastern, William; Mølvig, Jens; Mandrup-Poulsen, Thomas; Dinarello, Charles A.; Nielsen, Jens Høiriis; Nerup, Jørn

doi:10.1007/bf00279615

Cited by 91 publications

(47 citation statements)

References 33 publications

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“…Similar findings were observed in INS-1E cells exposed to thapsigargin or cytokines (IFN-γ plus IL-1β) and in primary beta cells exposed to the same agents. Cytokines inhibit Ins1/2 mRNA expression and pro-insulin biosynthesis in rat and mouse islets [46][47][48]. The decrease in Ins1/2 levels is secondary to NO production [22], a finding confirmed in the present study.…”

Section: Discussionsupporting

confidence: 87%

Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs

et al. 2007

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Aims/hypothesis Pancreatic beta cells respond to endoplasmic reticulum (ER) stress by activating the unfolded protein response. If the stress is prolonged, or the adaptive response fails, apoptosis is triggered. We used a 'homemade' microarray specifically designed for the study of beta cell apoptosis (the APOCHIP) to uncover mechanisms regulating beta cell responses to ER stress. Materials and methods A time course viability and microarray analysis was performed in insulin-producing INS-1E cells exposed to the reversible ER stress inducer cyclopiazonic acid (CPA). Modification of selected genes was confirmed by real-time RT-PCR, and the observed inhibition of expression of the insulin-1 (Ins1) and insulin-2 (Ins2) genes was further characterised in primary beta cells exposed to a diverse range of agents that induce ER stress. Results CPA-induced ER stress modified the expression of 183 genes at one or more of the time points studied. The expression of most of these genes returned to control levels after a 3 h recovery period following CPA removal, with all cells surviving. Two groups of genes were particularly affected by CPA, namely, those related to cellular responses to ER stress, which were mostly upregulated, and those related to differentiated beta cell functions, which were downregulated. Levels of Ins1 and Ins2 mRNAs were severely decreased in response to CPA treatment as a result of degradation, and there was a concomitant increase in the level of IRE1 activation. Conclusions/interpretation In this study we provide the first global analysis of beta cell molecular responses to a severe ER stress, and identify the early degradation of mRNA transcripts of the insulin genes as an important component of this response.

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Section: Discussionsupporting

confidence: 87%

Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs

et al. 2007

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“…Protein synthesis, chaperones, and protein folding. Several studies have shown IL-1 to influence gene transcription and protein synthesis (12,14,25,43) and have shown IL-1 to cause a fall in the overall rate of protein synthesis and of preproinsulin biosynthesis in particular (44).…”

Section: Discussionmentioning

confidence: 99%

Proteome Analysis of Interleukin-1β–Induced Changes in Protein Expression in Rat Islets of Langerhans

et al. 2001

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The intracellular molecular events involved in the ␤-cell death process are complex but poorly understood. Cytokines, e.g., interleukin (IL)-1␤, may play a crucial role in inducing this process. Protein synthesis is necessary for the deleterious effect of IL-1, and induction of both protective and deleterious proteins has been described. To characterize the rather complex pattern of islet protein expression in rat islets in response to IL-1, we have attempted to identify proteins of altered expression level after IL-1 exposure by 2D gel electrophoresis and mass spectrometry. Of 105 significantly changed (i.e., up-or downregulated or de novo-induced) protein spots, we obtained positive protein identification for 60 protein spots. The 60 identifications corresponded to 57 different proteins. Of these, 10 proteins were present in two to four spots, suggesting that posttranslatory modifications had occurred. In addition, 11 spots contained more than one protein. The proteins could be classified according to their function into the following groups: 1) energy transduction; 2) glycolytic pathway; 3) protein synthesis, chaperones, and protein folding; and 4) signal transduction, regulation, differentiation, and apoptosis. In conclusion, valuable information about the molecular mechanisms involved in cytokine-mediated ␤-cell destruction was obtained by this approach. Protein synthesis inhibitors (e.g., cycloheximide) effectively protect IL-1-exposed islets from destruction (12). Hence, protein synthesis is necessary for the deleterious effect of IL-1. Previous studies have shown that IL-1 induces the synthesis of members of the heat shock protein (HSP) family, like heme oxygenase (13) and HSPs 70 and 90 (14,15), and hyperexpression of HSPs in islets is partially protective against cytokine-induced ␤-cell destruction (16). Furthermore, it has been reported that IL-1 may induce the synthesis of unknown proteins with molecular weights of 45,50, 75, 85, 95, and 120 kDa (17). It has previously been shown that rat islets exposed to IL-1 release NO into the culture media (18). iNOS has been cloned from islets (19) in which it has been shown to be inducible in ␤-cells only (20). We have further shown that IL-1 also upregulates IL-1 converting enzyme mRNA transcription (21) in rat islets. Also, SOD is shown to be upregulated in islets by cytokines (15,22).Based on ␤-cell-selective toxic effects, we hypothesized that IL-1 induces a rather complex pattern of both protective and deleterious events and mechanisms in islets cells, and that in ␤-cells the deleterious events seem to prevail (23). We further suggested that this might be reflected at the level of islet protein expression (24). To examine this hypothesis, we used 2D gel electrophoresis to produce a database of rat islet proteins containing about 2,200 protein spots characterized by molecular weight and isoelectric point (pI). The data presented here provide the first global assessment of the IL-1-mediated ␤-cell-damaging processes at the protein level. We could demonstra...

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“…IL-1β has been shown to inhibit gene transcription and protein synthesis [13,33] and to decrease preproinsulin biosynthesis in particular [34]. Therefore, a global decrease in protein synthesis could reduce the capacity of a beta cell to survive IL-1β exposure.…”

Section: Protein Synthesis Chaperones and Protein Foldingmentioning

confidence: 99%

Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1?

et al. 2004

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Aim/hypothesis. Type 1 diabetes mellitus (T1DM) is caused by specific destruction of the pancreatic beta cells in the islets of Langerhans. Increased sensitivity to cytokines, in particular to interleukin-1β (IL-1β) seems to be an acquired trait during beta-cell maturation. In response to cytokines both protective and deleterious mechanisms are induced in beta cells, and when the deleterious prevail, T1DM develops. The aims of this study were to identify perturbation in protein patterns (PiPP) associated with beta-cell maturation, and compare these changes to previous analyses of IL-1β exposed rat islets. For this purpose, proteome analyses were carried out using a cell-line, which matures from a glucagon-producing pre-beta-cell phenotype (NHI-glu) to an insulin-producing beta-cell phenotype (NHI-ins). We have previously shown that this maturation is accompanied by acquired sensitivity to the toxic effects of IL-1β.Methods. 2D-gel electrophoresis was used to separate the proteins and MALDI-MS and database searches were performed to identify the proteins. Results. During beta-cell maturation 135 protein spots out of 2239 detectable changed expression levels. Of these, 74 were down-regulated, 44 up-regulated, 16 were suppressed and 1 was expressed de novo. Using MALDI-MS, positive identification was obtained for 93 out of the 135 protein-spots revealing 97 different proteins. Of these, 22 proteins were in common with changes identified in previous proteome analysis of perturbation in protein pattern in IL-1β exposed rat islets. Several of the proteins were present in more than one spot suggesting post-translational modification. Conclusion/interpretation. Several proteins and protein modifications were identified that could be critically involved in beta-cell maturation, insulin-gene expression and the acquired IL-1β sensitivity. [Diabetologia (2004) A. E. Karlsen ( ✉ ), Steno Diabetes Center, Niels Steensensvej 2, 2820 Gentofte, Denmark E-mail: aek@novonordisk.com Abbreviations: T1DM, Type 1 diabetes mellitus; PiPP, perturbation in protein pattern; NO, nitric oxide; iNOS, inducible nitric oxide synthase; 2D-GE, 2 dimensional gel electrophoresis; IEF, isoelectric focusing; NEPHGE, non-equilibrium pH-gradient electrophoresis; WF, Wistar Furth; BB, Bio Breeding; PDX-1, pancreatic duodenum homeobox 1; ASS, argininosuccinate synthetase; HSP, heat shock protein; Picot, PKC-interacting cousin of thioredoxin; JNK, Jun N-terminal kinase; VDAC, voltage-dependent anion channel; GST, glutathione-Stransferase; Mw, molecular weight; pI, isoelectric point. Diabetologia (2004) 47:62-74 DOI 10.1007/s00125-003-1277 Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1β Autoimmune Type 1 diabetes mellitus (T1DM) is caused by specific destruction of the insulin-producing beta cells in the islets of Langerhans in the pancreas [1]. During this process the islets are infiltrated with macrophages and lymphocytes, and these cells release a mixture of cytokines, such as inte...

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Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans

Cited by 91 publications

References 33 publications

Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs

Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs

Proteome Analysis of Interleukin-1β–Induced Changes in Protein Expression in Rat Islets of Langerhans

Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1?

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