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01.12.2004 | Article

Gene expression profiles during beta cell maturation and after IL-1β exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1β sensitivity

verfasst von: K. Nielsen, M. Kruhøffer, T. Ørntoft, T. Sparre, H. Wang, C. Wollheim, M. C. Jørgensen, J. Nerup, A. E. Karlsen

Erschienen in: Diabetologia | Ausgabe 12/2004

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Abstract

Aim/hypothesis

Maturation of the beta cells in the islets of Langerhans is dependent upon sequential activation of different transcription factors such as Pdx-1 and Nkx6.1. This maturation is associated with an acquired sensitivity to cytokines and may eventually lead to type 1 diabetes. The aims of this study were to characterise changes in mRNA expression during beta cell maturation as well as after interleukin-1β (IL-1β) exposure.

Methods

Transcriptome analyses were performed on two phenotypes characterised as a glucagon-producing pre-beta-cell phenotype (NHI-glu), which matures to an IL-1β-sensitive insulin-producing beta cell phenotype (NHI-ins). Beta cell lines over-expressing Pdx-1 or Nkx6.1, respectively, were used for functional characterisation of acquired IL-1β sensitivity.

Results

During beta cell maturation 98 fully annotated mRNAs changed expression levels. Of these, 50 were also changed after 24 h of IL-1β exposure. In addition, 522 and 197 fully annotated mRNAs, not affected by maturation, also changed expression levels following IL-1β exposure of the beta cell and the pre-beta-cell phenotype, respectively. Beta cell maturation was associated with an increased expression of Nkx6.1, whereas both Pdx-1 and Nkx6.1 expression were decreased following IL-1β exposure. Over-expression of Nkx6.1 or Pdx-1 in cell lines resulted in a significantly increased sensitivity to IL-1β.

Conclusions/interpretation

These results suggest that the final beta cell maturation accompanied by increased IL-1β sensitivity is, in part, dependent upon the expression of genes regulated by Pdx-1 and Nkx6.1. Future classification of the genes regulated by these transcription factors and changed during beta cell maturation should elucidate their role in the acquired sensitivity to IL-1β and may be helpful in identifying new targets for intervention/prevention strategies.

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Pictet RL, Rutter WJ (1972) Development of the embryonic endocrine pancreas. Handb Physiol 1:25–66

Servitja JM, Ferrer J (2004) Transcriptional networks controlling pancreatic development and beta cell function. Diabetologia 47:597–613CrossRefPubMed

Herrera PL (2000) Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages. Development 127:2317–2322PubMed

Jensen J, Heller RS, Funder-Nielsen T et al. (2000) Independent development of pancreatic alpha- and beta-cells from neurogenin 3-expressing precursors: a role for the Notch pathway in repression of premature differentiation. Diabetes 49:163–176PubMed

Offield MF, Jetton TL, Labosky PA et al. (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122:983–995PubMed

Guz Y, Montminy MR, Stein R et al. (1995) Expression of murine STF-1, a putative insulin gene transcription factor, in beta cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development 121:11–18PubMed

Oster A, Jensen J, Serup P et al. (1998) Rat endocrine pancreatic development in relation to two homeobox gene products (Pdx-1 and Nkx 6.1). J Histochem Cytochem 46:707–715PubMed

Nerup J, Mandrup-Poulsen T, Helqvist S et al. (1994) On the pathogenesis of IDDM. Diabetologia 37 Suppl 2:S82–S89CrossRef

Mandrup-Poulsen T (1996) The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 39:1005–1029CrossRefPubMed

10.

Rabinovitch A, Suarez-Pinzon WL, Strynadka K, Lakey JR, Rajotte RV (1996) Human pancreatic islet beta-cell destruction by cytokines involves oxygen free radicals and aldehyde production. J Clin Endo Met 81:3197–3202CrossRef

11.

Delaney CA, Pavlovic D, Hoorens A, Pipeleers DG, Eizirik DL (1997) Cytokines induce deoxyribonucleic acid strand breaks and apoptosis in human pancreatic islet cells. Endocrinology 138:2610–2614CrossRefPubMed

12.

Sandler S, Bendtzen K, Borg L et al. (1989) Studies on the mechanism causing inhibition of insulin secretion in rat pancreatic islets exposed to interleukin-1β indicate a perturbation in the mitochondrial function. Endocrinology 124:1492–1501PubMed

13.

Cavallo MG, Monetini L, Valente L et al. (1997) Glutathione protects a human insulinoma cell line from tumor necrosis factor-alpha-mediated cytotoxicity. J Clin Lab Res 27:44–47

14.

Lortz S, Tiedge M, Nachtwey T et al. (2000) Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes. Diabetes 49:1123–1130PubMed

15.

Chen HN, Carlson EC, Pellet L, Moritz JT, Epstein PN (2001) Overexpression of metallothionein in pancreatic beta-cells reduces streptozotocin-induced DNA damage and diabetes. Diabetes 50:2040–2046PubMed

16.

Madsen OD, Andersen LC, Michelsen B et al. (1988) Tissue-specific expression of transfected human insulin genes in pluripotent clonal rat lines induced during passage in vivo. Proc Natl Acad Sci USA 85:6652–6656

17.

Madsen OD, Andersen LC, Serup P, Michelsen B (1989) Control of insulin gene expression in pluripotent rat islet tumor cells. Elsevier, Biomedical Division, pp 141–153

18.

Nielsen K, Karlsen AE, Deckert M et al. (1999) Beta-cell maturation leads to in vitro sensitivity to cytotoxins. Diabetes 48:2324–2332PubMed

19.

Nielsen K, Sparre T, Larsen MR et al. (2004) Protein expression changes in a cell system of beta-cell maturation reflect an acquired sensitivity to IL-1β. Diabetologia 47t:62–74CrossRef

20.

Lockhart DJ, Dong H, Byrne MC et al. (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 14:1675–1680PubMed

21.

Mose Larsen P, Fey SJ, Larsen MR et al. (2001) Proteome analysis of interleukin-1β-induced changes in protein expression in rat islets of Langerhans. Diabetes 50:1056–1063PubMed

22.

Sparre T, Christensen UB, Larsen PM et al. (2002) IL-1β induced protein changes in diabetes prone BB rat islets of Langerhans identified by proteome analysis. Diabetologia 45:1550–1561CrossRefPubMed

23.

Rieneck K, Bovin LF, Josefsen K et al. (2000) Massive parallel gene expression profiling of RINm5F pancreatic islet β-cells stimulated with interleukin-1β. APMIS 108:855–872PubMed

24.

Cardozo AK, Kruhoffer M, Leeman R, Orntoft T, Eizirik DL (2001) Identification of novel cytokine-induced genes in pancreatic β-cells by high-density oligonucleotide arrays. Diabetes 50:909–920PubMed

25.

Kutlu B, Cardozo AK, Darville MI et al. (2003) Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells. Diabetes 52:2701–2719PubMed

26.

Jensen J, Serup P, Karlsen C, Nielsen TF, Madsen OD (1996) mRNA profiling of rat islet tumors reveals Nkx6.1 as a β-cell-specific homeodomain transcription factor. J Biol Chem 271:18749–18758CrossRefPubMed

27.

Wang HY, Maechler P, Ritz-Laser B et al. (2001) Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. J Biol Chem 276:25279–25286CrossRefPubMed

28.

Jørgensen MC, Vestergard-Petersen H, Ericson J, Madsen OD, Serup P (1999) Cloning and DNA-binding properties of the rat pancreatic beta-cell-specific factor Nkx6.1. FEBS Lett 461:287–294CrossRefPubMed

29.

Madsen OD, Larsson L-I, Rehfeld JF et al. (1986) Cloned cell lines from a transplantable islet cell tumor are heterogeneous and express cholecystokinin in addition to islet hormones. J Cell Biol 103:2025–2034CrossRefPubMed

30.

Blume N, Skouv J, Larsson L-I, Holst JJ, Madsen OD (1995) Potent inhibitory effects of transplantable rat glucagonamas and insulinomas on the respective endogenous islet cells are associated with pancreatic apoptosis. J Clin Invest 96:2227–2235PubMed

31.

Serup P, Petersen HV, Pedersen EE et al. (1995) 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 310:997–1003PubMed

32.

Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J Immunol Methods 65:55–63CrossRefPubMed

33.

Kim CH, Kim DK, Choi SJ et al. (2003) Proteomic and transcriptomic analysis of interleukin-1 beta treated lung carcinoma cell line. Proteomics 3:2454–2471CrossRefPubMed

34.

Sander N, Sussel L, Conners J et al. (2000) Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of β-cell formation in the pancreas. Development 127:5533–5540PubMed

35.

Ferrer J, Gomis R, Fernandez Alvarez J, Casamitjana R, Vilardell E (1993) Signals derived from glucose metabolism are required for glucose regulation of pancreatic islet GLUT2 mRNA and protein. Diabetes 42:1273–1280PubMed

36.

Yoshikawa H, Tajiri Y, Sako Y et al. (2001) Effects of free fatty acids on beta-cell functions: a possible involvement of peroxisome proliferator-activated receptors alpha or pancreatic/duodenal homeobox. Metab Clin Exp 50:613–618PubMed

37.

Guillam MT, Hümmler E, Schaerer E et al. (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17:327–330

38.

Hagar RE, Ehrlich BE (2000) Regulation of the type III InsP₃ receptor and its role in β-cell function. Cell Mol Life Sci 57:1938–1949PubMed

39.

Laybutt DR, Glandt M, Xu G et al. (2003) Critical reduction in beta-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes. J Biol Chem 278:2997–3005CrossRefPubMed

40.

Laybutt DR, Weir GC, Kaneto H et al. (2002) Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 51:1793–1804PubMed

41.

Noguchi K, Kitanaka C, Yamana H et al. (1999) Regulation of c-Myc through phosphorylation at Ser-62 and Ser-71 by c-Jun N-terminal kinase. J Biol Chem 274:32580–32587CrossRefPubMed

42.

Noguchi K, Yamana H, Kitanaka C et al. (2000) Differential role of the JNK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. Biochem Biophys Res Commun 267:221–227CrossRefPubMed

43.

Ammendrup A, Maillard A, Nielsen K et al. (2000) The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes 49:1468–1476PubMed

44.

Rothe H, Hibino T, Itoh Y, Kolb H, Martin S (1997) Systemic production of interferon-gamma inducing factor (IGIF) versus local IFN-gamma expression involved in the development of Th1 insulitis in NOD mice. J Autoimmun 10:251–256CrossRefPubMed

45.

Hong TP, Andersen NA, Nielsen K et al. (2000) Interleukin-18 mRNA, but not interleukin-18 receptor mRNA, is constitutively expressed in islet beta-cells and upregulated by interferon-gamma. Eur Cytokine Netw 11:193–205PubMed

46.

Hoek RH, Ruuls SR, Murphy CA et al. (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290:1768–1771CrossRefPubMed

47.

Barclay AN, Wright GJ, Brooke G, Brown MH (2002) CD200 and membrane protein E interactions in the control of myeloid cells. Trends Immunol 23:285–290CrossRefPubMed

48.

Hevroni D, Rattner A, Bundman M et al. (1998) Hippocampal plasticity involves extensive gene induction and multiple cellular mechanisms. J Mol Neurosci 10:75–98

49.

Flodström-Tullberg M, Yadav D, Hagerkvist R et al. (2003) Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. Diabetes 52:2696–2700PubMed

50.

Karlsen AE, Ronn SG, Lindberg K et al. (2001) Suppressor of cytokine signaling 3 (SOCS-3) protects beta cells against interleukin-1β- and interferon-γ-mediated toxicity. Proc Natl Acad Sci USA 98:12191–12196CrossRefPubMed

51.

Kobayashi K, Rosenbloom C, Beaudet AL, O’Brien WE (1991) Additional mutations in argininosuccinate synthetase causing citrullinemia. Mol Biol Med 8:95–100PubMed

52.

Sener A, Blachier F, Malaisse WJ (1988) Production of urea but absence of urea cycle in pancreatic islet cells. Med Sci Res 16:483–484

53.

Powers-Lee SG, Meister A (1988) Urea synthesis and ammonia metabolism. In: Jakoby WB, Popper H, Schachter D, Shafritz DA (eds) The liver and pathobiology (2nd edition). Raven Press, New York pp 317–330

54.

Mill JF, Mearow KM, Purohit HJ et al. (1991) Cloning and functional characterization of the rat glutamine synthetase gene. Brain Res Mol Brain Res 9:197–207CrossRefPubMed

55.

Wu G, Morris SM (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

56.

Guthmiller P, Van-Pilsum JF, Boen JR, McGuire DM (1994) Cloning and sequencing of rat kidney l-arginine:glycine amidinotransferase. Studies on the mechanism of regulation by growth hormone and creatine. J Biol Chem 269:17556–17560PubMed

57.

Eizirik DL, Pavlovic D (1997) Is there a role for nitric-oxide in beta-cell dysfunction and damage in IDDM. Diabetes Metab Res Rev 13:293–307CrossRef

58.

Nussler AK, Billiar TR, Liu ZZ, Morris SM (1994) Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. Implications for regulation of nitric oxide production. J Biol Chem 269:1257–1261PubMed

59.

Wu GY, Brosnan JT (1992) Macrophages can convert citrulline into arginine. Biochem J 281:45–48PubMed

60.

Flodström M, Chen MC, Smismans A et al. (1999) Interleukin-1β increases arginine accumulation and activates the citrulline-NO cycle in rat pancreatic beta cells. Cytokine 11:400–407CrossRefPubMed

61.

Dickinson DA, Forman HJ (2002) Glutathione in defense and signaling: lessons from a small thiol. Ann NY Acad Sci 973:488–504

62.

Malaisse WJ, Malaisse-Lagae F, Sener A, Pipeleers DG (1982) Determinants of the selective toxicity of alloxan to the pancreatic β-cell. Proc Natl Acad Sci USA 79:927–930

63.

Lenzen S, Drinkgern J, Tiedge M (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463–466CrossRefPubMed

Titel: Gene expression profiles during beta cell maturation and after IL-1β exposure reveal important roles of Pdx-1 and Nkx6.1 for IL-1β sensitivity
verfasst von: K. Nielsen
M. Kruhøffer
T. Ørntoft
T. Sparre
H. Wang
C. Wollheim
M. C. Jørgensen
J. Nerup
A. E. Karlsen
Publikationsdatum: 01.12.2004
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 12/2004
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-004-1578-1

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