Protein Expression Changes in a Cell System of Beta-cell Maturation Reflect an Acquired Sensitivity to IL-1beta

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2003 Dec 4

PMID 14652719

Citations 8

Authors

K Nielsen

T Sparre

M R Larsen

M Nielsen

S J Fey

P Mose Larsen

P Roepstorff

J Nerup

A E Karlsen

Affiliations

Soon will be listed here.

Abstract

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-1beta (IL-1beta) 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-1beta 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-1beta.

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-1beta 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-1beta sensitivity.

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References

Delaney C, Pavlovic D, Hoorens A, Pipeleers D, Eizirik D . Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology. 1997; 138(6):2610-4. DOI: 10.1210/endo.138.6.5204. View

Hodge T, Colombini M . Regulation of metabolite flux through voltage-gating of VDAC channels. J Membr Biol. 1997; 157(3):271-9. DOI: 10.1007/s002329900235. View

Jensen O, Larsen M, Roepstorff P . Mass spectrometric identification and microcharacterization of proteins from electrophoretic gels: strategies and applications. Proteins. 1998; Suppl 2:74-89. DOI: 10.1002/(sici)1097-0134(1998)33:2+<74::aid-prot9>3.3.co;2-2. View

Herrera P, Huarte J, Zufferey R, Nichols A, Mermillod B, Philippe J . Ablation of islet endocrine cells by targeted expression of hormone-promoter-driven toxigenes. Proc Natl Acad Sci U S A. 1994; 91(26):12999-3003. PMC: 45568. DOI: 10.1073/pnas.91.26.12999. View

Burkart V, Liu H, Bellmann K, Wissing D, Jaattela M, Cavallo M . Natural resistance of human beta cells toward nitric oxide is mediated by heat shock protein 70. J Biol Chem. 2000; 275(26):19521-8. DOI: 10.1074/jbc.M002265200. View

Oberhammer F, Hochegger K, Froschl G, Tiefenbacher R, Pavelka M . Chromatin condensation during apoptosis is accompanied by degradation of lamin A+B, without enhanced activation of cdc2 kinase. J Cell Biol. 1994; 126(4):827-37. PMC: 2120132. DOI: 10.1083/jcb.126.4.827. View

Shimizu S, Narita M, Tsujimoto Y . Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 1999; 399(6735):483-7. DOI: 10.1038/20959. View

GEPTS W . Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965; 14(10):619-33. DOI: 10.2337/diab.14.10.619. View

Larsen P, Fey S, Larsen M, Nawrocki A, Andersen H, KAHLER H . Proteome analysis of interleukin-1beta--induced changes in protein expression in rat islets of Langerhans. Diabetes. 2001; 50(5):1056-63. DOI: 10.2337/diabetes.50.5.1056. View

10.

Serup P, Petersen H, PEDERSEN E, Edlund H, Leonard J, Petersen J . The homeodomain protein IPF-1/STF-1 is expressed in a subset of islet cells and promotes rat insulin 1 gene expression dependent on an intact E1 helix-loop-helix factor binding site. Biochem J. 1995; 310 ( Pt 3):997-1003. PMC: 1135994. DOI: 10.1042/bj3100997. View

11.

Jensen O, Podtelejnikov A, Mann M . Identification of the components of simple protein mixtures by high-accuracy peptide mass mapping and database searching. Anal Chem. 1997; 69(23):4741-50. DOI: 10.1021/ac970896z. View

12.

Offield M, Jetton T, Labosky P, Ray M, Stein R, Magnuson M . PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development. 1996; 122(3):983-95. DOI: 10.1242/dev.122.3.983. View

13.

Rabinovitch A, Suarez-Pinzon W, Strynadka K, Lakey J, Rajotte R . Human pancreatic islet beta-cell destruction by cytokines involves oxygen free radicals and aldehyde production. J Clin Endocrinol Metab. 1996; 81(9):3197-202. DOI: 10.1210/jcem.81.9.8784069. View

14.

Tiedge M, Lortz S, Drinkgern J, Lenzen S . Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes. 1997; 46(11):1733-42. DOI: 10.2337/diab.46.11.1733. View

15.

Scarim A, Heitmeier M, Corbett J . Heat shock inhibits cytokine-induced nitric oxide synthase expression by rat and human islets. Endocrinology. 1998; 139(12):5050-7. DOI: 10.1210/endo.139.12.6366. View

16.

Jensen J, Serup P, Karlsen C, Nielsen T, Madsen O . mRNA profiling of rat islet tumors reveals nkx 6.1 as a beta-cell-specific homeodomain transcription factor. J Biol Chem. 1996; 271(31):18749-58. DOI: 10.1074/jbc.271.31.18749. View

17.

Nalivaeva N, Turner A . Post-translational modifications of proteins: acetylcholinesterase as a model system. Proteomics. 2001; 1(6):735-47. DOI: 10.1002/1615-9861(200106)1:6<735::AID-PROT735>3.0.CO;2-8. View

18.

Flodstrom M, Chen M, Smismans A, Schuit F, Pipeleers D, Eizirik D . Interleukin 1beta increases arginine accumulation and activates the citrulline-NO cycle in rat pancreatic beta cells. Cytokine. 1999; 11(6):400-7. DOI: 10.1006/cyto.1998.0446. View

19.

Shevchenko A, Wilm M, Vorm O, Mann M . Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels. Anal Chem. 1996; 68(5):850-8. DOI: 10.1021/ac950914h. View

20.

Mandrup-Poulsen T . The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia. 1996; 39(9):1005-29. DOI: 10.1007/BF00400649. View