[en] IL-1beta and TNF-alpha contribute to pancreatic beta cell death in type 1 diabetes. Both cytokines activate the transcription factor nuclear factor-kappaB (NF-kappaB), but recent observations suggest that NF-kappaB blockade prevents IL-1beta + IFN-gamma- but not TNF-alpha + IFN-gamma-induced beta cell apoptosis. The aim of the present study was to compare the effects of IL-1beta and TNF-alpha on cell death and the pattern of NF-kappaB activation and global gene expression in beta cells. METHODS: Cell viability was measured after exposure to IL-1beta or to TNF-alpha alone or in combination with IFN-gamma, and blockade of NF-kappaB activation or protein synthesis. INS-1E cells exposed to IL-1beta or TNF-alpha in time course experiments were used for IkappaB kinase (IKK) activation assay, detection of p65 NF-kappaB by immunocytochemistry, real-time RT-PCR and microarray analysis. RESULTS: Blocking NF-kappaB activation protected beta cells against IL-1beta + IFNgamma- or TNFalpha + IFNgamma-induced apoptosis. Blocking de novo protein synthesis did not increase TNF-alpha- or IL-1beta-induced beta cell death, in line with the observations that cytokines induced the expression of the anti-apoptotic genes A20, Iap-2 and Xiap to a similar extent. Microarray analysis of INS-1E cells treated with IL-1beta or TNF-alpha showed similar patterns of gene expression. IL-1beta, however, induced a higher rate of expression of NF-kappaB target genes putatively involved in beta cell dysfunction and death and a stronger activation of the IKK complex, leading to an earlier translocation of NF-kappaB to the nucleus. CONCLUSIONS/INTERPRETATION: NF-kappaB activation in beta cells has a pro-apoptotic role following exposure not only to IL-1beta but also to TNF-alpha. The more marked beta cell death induced by IL-1beta is explained at least in part by higher intensity NF-kappaB activation, leading to increased transcription of key target genes.
Research Center/Unit :
Giga-Signal Transduction - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Ortis, Fernanda; Université Libre de Bruxelles - ULB > Laboratory of Experimental Medicine
Pirot, P.; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Naamane, N.; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Thomas HE, Kay TW (2000) Beta cell destruction in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse. Diabetes Metab Res Rev 16:251-261
Eizirik DL, Mandrup-Poulsen T (2001) A choice of death-the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44:2115-2133
Cnop M, Welsh N, Jonas JC et al (2005) Mechanisms of pancreatic beta cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97-S107
Ortis F, Cardozo AK, Crispim D, Storling J, Mandrup-Poulsen T, Eizirik DL (2006) Cytokine-induced pro-apoptotic gene expression in insulin-producing cells is related to rapid, sustained and non-oscillatory NF-κB activation. Mol Endocrinol 20:1867-1879
Giannoukakis N, Rudert WA, Trucco M, Robbins PD (2000) Protection of human islets from the effects of interleukin-1β by adenoviral gene transfer of an IκB repressor. J Biol Chem 275:36509-36513
Heimberg H, Heremans Y, Jobin C et al (2001) Inhibition of cytokine-induced NF-κB activation by adenovirus-mediated expression of a NF-κB super-repressor prevents beta cell apoptosis. Diabetes 50:2219-2224
Eldor R, Yeffet A, Baum K et al (2006) Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci U S A 103:5072-5077
Cardozo AK, Heimberg H, Heremans Y et al (2001) A comprehensive analysis of cytokine-induced and nuclear factor-κB-dependent genes in primary rat pancreatic beta-cells. J Biol Chem 276:48879-48886
Cardozo AK, Ortis F, Storling J et al (2005) Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta cells. Diabetes 54:452-461
Pirot P, Ortis F, Cnop M et al (2007) Transcriptional regulation of the endoplasmic reticulum stress gene Chop in pancreatic insulin-producing cells. Diabetes 56:1069-1077
Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42-61
Karin M, Lin A (2002) NF-κB at the crossroads of life and death. Nat Immunol 3:221-227
Dutta J, Fan Y, Gupta N, Fan G, Gelinas C (2006) Current insights into the regulation of programmed cell death by NF-κB. Oncogene 25:6800-6816
Kim S, Millet I, Kim HS et al (2007) NF-κB prevents beta cell death and autoimmune diabetes in NOD mice. Proc Natl Acad Sci U S A 104:1913-1918
Hoffmann A, Leung TH, Baltimore D (2003) Genetic analysis of NF-κB/Rel transcription factors defines functional specificities. EMBO J 22:5530-5539
Saccani S, Pantano S, Natoli G (2003) Modulation of NF-κB activity by exchange of dimers. Mol Cell 11:1563-1574
Hayden MS, Ghosh S (2004) Signaling to NF-κB. Genes Dev 18:2195-2224
Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132:344-362
Vermeulen L, De Wilde G, Notebaert S, Van den Berghe W, Haegeman G (2002) Regulation of the transcriptional activity of the nuclear factor-κB p65 subunit. Biochem Pharmacol 64:963-970
Andersen NA, Larsen CM, Mandrup-Poulsen T (2000) TNFα and IFNγ potentiate IL-1β induced mitogen activated protein kinase activity in rat pancreatic islets of Langerhans. Diabetologia 43:1389-1396
Larsen L, Storling J, Darville M et al (2005) Extracellular signal-regulated kinase is essential for interleukin-1-induced and nuclear factor κB-mediated gene expression in insulin-producing INS-1E cells. Diabetologia 48:2582-2590
Beg AA, Baltimore D (1996) An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274:782-784
Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNF-α-induced apoptosis by NF-κB. Science 274:787-789
Muppidi JR, Tschopp J, Siegel RM (2004) Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction. Immunity 21:461-465
Pipeleers DG, in't Veld PA, Van de Winkel M, Maes E, Schuit FC, Gepts W (1985) A new in vitro model for the study of pancreatic A and B cells. Endocrinology 117:806-816
Rasschaert J, Ladriere L, Urbain M et al (2005) Toll-like receptor 3 and STAT-1 contribute to double-stranded RNA + interferon-γ-induced apoptosis in primary pancreatic beta-cells. J Biol Chem 280:33984-33991
Janjic D, Maechler P, Sekine N, Bartley C, Annen AS, Wolheim CB (1999) Free radical modulation of insulin release in INS-1 cells exposed to alloxan. Biochem Pharmacol 57:639-648
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 52:2701-2719
Cardozo AK, Kruhoffer M, Leeman R, Orntoft T, Eizirik DL (2001) Identification of novel cytokine-induced genes in pancreatic beta-cells by high-density oligonucleotide arrays. Diabetes 50:909-920
Cnop M, Ladriere L, Hekerman P et al (2007) Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. J Biol Chem 282:3989-3997
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite, and nitrate in biological fluids. Anal Biochem 126:131-138
Jobin C, Panja A, Hellerbrand C et al (1998) Inhibition of proinflammatory molecule production by adenovirus-mediated expression of a nuclear factor κB super-repressor in human intestinal epithelial cells. J Immunol 160:410-418
Hoorens A, Stange G, Pavlovic D, Pipeleers D (2001) Distinction between interleukin-1-induced necrosis and apoptosis of islet cells. Diabetes 50:551-557
Magnusson NE, Cardozo AK, Kruhoffer M, Eizirik DL, Orntoft TF, Jensen JL (2005) Construction and validation of the APOCHIP, a spotted oligo-microarray for the study of beta-cell apoptosis. BMC Bioinformatics 6:311
Pirot P, Naamane N, Libert F et al (2007) Global profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs. Diabetologia 50:1006-1014
Darville MI, Eizirik DL (1998) Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia 41:1101-1108
Dooley TP, Curto EV, Davis RL, Grammatico P, Robinson ES, Wilborn TW (2003) DNA microarrays and likelihood ratio bioinformatic methods: discovery of human melanocyte biomarkers. Pigment Cell Res 16:245-253
Liuwantara D, Elliot M, Smith MW et al (2006) Nuclear factor-κB regulates beta-cell death: a critical role for A20 in beta-cell protection. Diabetes 55:2491-2501
Mandrup-Poulsen T, Bendtzen K, Dinarello CA, Nerup J (1987) Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity. J Immunol 139:4077-4082
Flodstrom M, Welsh N, Eizirik DL (1996) Cytokines activate the nuclear factor kappa B (NF-kappa B) and induce nitric oxide production in human pancreatic islets. FEBS Lett 385:4-6
Liu D, Pavlovic D, Chen MC, Flodstrom M, Sandler S, Eizirik DL (2000) Cytokines induce apoptosis in beta-cells isolated from mice lacking the inducible isoform of nitric oxide synthase (iNOS-/-). Diabetes 49:1116-1122
Naamane N, van Helden J, Eizirik DL (2007) In silico identification of NF-κB-regulated genes in pancreatic beta-cells. BMC Bioinformatics 8:55
Hammar EB, Irminger JC, Rickenbach K et al (2005) Activation of NF-κB by extracellular matrix is involved in spreading and glucose-stimulated insulin secretion of pancreatic beta cells. J Biol Chem 280:30630-30637
Connelly L, Palacios-Callender M, Ameixa C, Moncada S, Hobbs AJ (2001) Biphasic regulation of NF-κB activity underlies the pro- and anti-inflammatory actions of nitric oxide. J Immunol 166:3873-3881
Nasuhara Y, Adcock IM, Catley M, Barnes PJ, Newton R (1999) Differential IκB kinase activation and IκBa degradation by interleukin-1β and tumor necrosis factor-α in human U937 monocytic cells. Evidence for additional regulatory steps in κB-dependent transcription. J Biol Chem 274:19965-19972
Chen LF, Greene WC (2004) Shaping the nuclear action of NF-κB. Nat Rev Mol Cell Biol 5:392-401
Pavlovic D, Andersen NA, Mandrup-Poulsen T, Eizirik DL (2000) Activation of extracellular signal-regulated kinase (ERK)1/2 contributes to cytokine-induced apoptosis in purified rat pancreatic beta-cells. Eur Cytokine Netw 11:267-274
Kim HS, Kim S, Lee MS (2005) IFN-γ sensitizes MIN6N8 insulinoma cells to TNF-α-induced apoptosis by inhibiting NF-κB-mediated XIAP upregulation. Biochem Biophys Res Commun 336:847-853
Kharroubi I, Lee CH, Hekerman P, Darville MI, Evans RM, Eizirik DL et al (2006) BCL-6: a possible missing link for anti-inflammatory PPAR-δ signalling in pancreatic beta cells. Diabetologia 49:2350-2358
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.