Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
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NF-${\kappa}B$ Inhibitor Suppresses Hypoxia-induced Apoptosis of Mouse Pancreatic ${\beta}$-cell Line MIN6

  • Koh, Hyun Sook (Department of Biological Science, Gachon University) ;
  • Kim, Jae Young (Department of Biological Science, Gachon University)
  • Received : 2014.03.16
  • Accepted : 2014.03.27
  • Published : 2014.03.31
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Abstract

Hypoxia is one of the main reasons for islet apoptosis after transplantation as well as during isolation. In this study, we attempted to determine the potential usefulness of NF-${\kappa}B$ inhibitor for suppression of hypoxia-induced ${\beta}$-cell apoptosis as well as the relationship between IP-10 induction and ${\beta}$-cell apoptosis in hypoxia. To accomplish this, we cultured the mouse pancreatic ${\beta}$-cell line MIN6 in hypoxia (1% $O_2$). Among several examined chemokines, only IP-10 mRNA expression was induced under hypoxia, and this induced IP-10 expression was due to NF-${\kappa}B$ activity. Since a previous study suggested that IP-10 mediates ${\beta}$-cell apoptosis, we measured hypoxia-induced IP-10 protein and examined the effect of anti-IP-10 neutralizing Ab on hypoxia-induced ${\beta}$-cell apoptosis. However, IP-10 protein was not detected, and anti-IP-10 neutralizing Ab did not rescue hypoxia-induced MIN6 apoptosis, indicating that there is no relationship between hypoxia-induced IP-10 mRNA expression and hypoxia-induced ${\beta}$-cell apoptosis. Since it was still not clear if NF-${\kappa}B$ functions as an apoptotic or anti-apoptotic mediator in hypoxia-induced ${\beta}$-cell apoptosis, we examined possible involvement of NF-${\kappa}B$ in hypoxia-induced ${\beta}$-cell apoptosis. Treatment with 1 ${\mu}M$ NF-${\kappa}B$ inhibitor suppressed hypoxiainduced apoptosis by more than 50%, while 10 ${\mu}M$ AP-1 or 4 ${\mu}M$ NF-AT inhibitor did not, indicating involvement of NF-${\kappa}B$ in hypoxia-induced ${\beta}$-cell apoptosis. Overall, these results suggest that IP-10 is not involved in hypoxia-induced ${\beta}$-cell apoptosis, and that NF-${\kappa}B$ inhibitor can be useful for ameliorating hypoxia-induced ${\beta}$-cell apoptosis.

Keywords

References

  1. Aida K, Nishida Y, Tanaka S, Maruyama T, Shimada A, Awata T, Suzuki M, Shimura H, Takizawa S, Ichijo M, Akiyama D, Furuya F, Kawaguchi A, Kaneshige M, Itakura J, Fujii H, Endo T, Kobayashi T. RIG-I- and MDA5-initiated innate immunity linked with adaptive immunity accelerates $\beta$-cell death in fulminant type 1 diabetes. Diabetes. 2011. 60: 884-889. https://doi.org/10.2337/db10-0795
  2. Baker MS, Chen X, Rotramel A, Nelson J, Kaufman DB. Proinflammatory cytokines induce NF-${\kappa}B$-dependent/NOindependent chemokine gene expression in MIN6 $\beta$ cells. J Surg Res. 2003. 110: 295-303. https://doi.org/10.1016/S0022-4804(03)00027-1
  3. Barshes NR, Lee T, Goodpasture S, Brunicardi FC, Alejandro R, Ricordi C, Soltes G, Barth M, Hamilton D, Goss JA. Achievement of insulin independence via pancreatic islet transplantation using a remote isolation center: A first-year review. Transplant Proc. 2004. 36: 1127-1129. https://doi.org/10.1016/j.transproceed.2004.04.057
  4. Buttmann M, Berberich-Siebelt F, Serfling E, Rieckmann P. Interferon-$\gamma$ is a potent inducer of interferon regulatory factor-1/2-dependent IP-10/CXCL10 expression in primary human endothelial cells. J Vasc Res. 2007. 44: 51-60. https://doi.org/10.1159/000097977
  5. Cantley J, Grey ST, Maxwell PH, Withers DJ. The hypoxia response pathway and $\beta$-cell function. Diabetes Obes Metabol. 2010. 12: 159-167. https://doi.org/10.1111/j.1463-1326.2010.01276.x
  6. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxiainducible factor-1 during hypoxia: A mechanism of $O_{2}$ sensing. J Biol Chem. 2000. 275: 25130-25138. https://doi.org/10.1074/jbc.M001914200
  7. Chang I, Kim S, Kim JY, Cho N, Kim YH, Kim HS, Lee MK, Kim KW, Lee MS. Nuclear factor ${\kappa}B$ protects pancreatic beta-cells from tumor necrosis factor-a-mediated apoptosis. Diabetes. 2003. 52: 1169-1175. https://doi.org/10.2337/diabetes.52.5.1169
  8. Cummins EP, Taylor CT. Hypoxia-responsive transcription factors. Pflugers Arch. 2005. 450: 363-371. https://doi.org/10.1007/s00424-005-1413-7
  9. de Groot M, Schuurs TA, Keizer PPM, Fekken S, Leuvenink HGD, van Schilfgaarde R. Response of encapsulated rat pancreatic islets to hypoxia. Cell Transplant. 2003. 12: 867-875. https://doi.org/10.3727/000000003771000219
  10. Desco MC, Asensi M, Marquez R, Martinez-Valls J, Vento M, Pallardo FV, Sastre J, Vina J. Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes. 2002. 51: 1118-1124. https://doi.org/10.2337/diabetes.51.4.1118
  11. Dionne KE, Colton CK, Yarmush ML. Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans. Diabetes. 1993. 42: 12-21. https://doi.org/10.2337/diab.42.1.12
  12. Eldor R, Yeffet A, Baum K, Doviner V, Amar D, Ben-Neriah Y, Christofori G, Peled A, Carel JC, Boitard C, Klein T, Serup P, Eizirik DL, Melloul D. Conditional and specific NF-kappa B blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci USA. 2006. 103: 5072-5077. https://doi.org/10.1073/pnas.0508166103
  13. Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, Messeguer X. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003. 31: 3651-3653. https://doi.org/10.1093/nar/gkg605
  14. Foncea R, Carvajal C, Almarza C, Leighton F. Endothelial cell oxidative stress and signal transduction. Biol Res. 2000. 33: 86-96.
  15. Fonseca SG, Burcin M, Gromada J, Urano F. Endoplasmic reticulum stress in $\beta$-cells and development of diabetes. Curr Opin Pharmacol. 2009. 9: 763-770. https://doi.org/10.1016/j.coph.2009.07.003
  16. Frossi B, Rivera J, Hirsch E, Pucillo C. Selective activation of Fyn/PI3K and p38 MAPK regulates IL-4 production in BMMC under nontoxic stress condition. J Immunol. 2007. 178: 2549-2555. https://doi.org/10.4049/jimmunol.178.4.2549
  17. Giannoukakis N, Rudert WA, Trucco M, Robbins PD. Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. J Biol Chem. 2000. 275: 36509-36513. https://doi.org/10.1074/jbc.M005943200
  18. Giuliani M, Moritz W, Bodmer E, Dindo D, Kugelmeier P, Lchmann R, Gassmann M, Groscurth P, Weber M. Central necrosis in isolated hypoxic human pancreatic islets: evidence for postisolation ischemia. Cell Transplant. 2005. 14: 67-76. https://doi.org/10.3727/000000005783983287
  19. Greijer AE, van der Wall E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol. 2004. 57: 1009-1014. https://doi.org/10.1136/jcp.2003.015032
  20. Han KY, Yang D, Chang EJ, Lee Y, Huang H, Sung SH, Lee ZH, Kim YC, Kim HH. Inhibition of osteoclast differentiation and bone resorption by sauchinone. Biochem Pharmacol. 2007. 74: 911-923. https://doi.org/10.1016/j.bcp.2007.06.044
  21. Heimberg H, Heremans Y, Jobin C, Leemans R, Cardozo AK, Darville M, Eizirik DL. Inhibition of cytokine-induced NF- ${\kappa}B$ activation by adenovirus mediated expression of NF-${\kappa}B$ super-repressor prevents beta-cell apoptosis. Diabetes. 2001. 50: 2219-2224. https://doi.org/10.2337/diabetes.50.10.2219
  22. Jia J, Liu Y, Zhang X, Liu X, Qi J. Regulation of iNOS expression by NF-kappaB in human lens epithelial cells treated with high levels of glucose. Invest Ophth Vis Sci. 2013. 54: 5070-5077. https://doi.org/10.1167/iovs.13-11796
  23. Johansson U, Olsson A, Gabrielsson S, Nilsson B, Korsgren O. Inflammatory mediators expressed in human islets of Langerhans: implications for islet transplantation. Biochem Biophys Res Commun. 2003. 308: 474-479. https://doi.org/10.1016/S0006-291X(03)01392-5
  24. Kim D, Kim YJ, Koh HS, Jang TY, Park HE, Kim JY. Reactive oxygen species enhance TLR10 expression in the human monocytic cell line THP-1. Int J Mol Sci. 2010. 11: 3769-3782. https://doi.org/10.3390/ijms11103769
  25. Kim S, Millet I, Kim HS, Kim JY, Han MS, Lee MK, Kim KW, Sherwin RS, Karin M, Lee MS. NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice. Proc Natl Acad Sci USA. 2007. 104: 1913-1918. https://doi.org/10.1073/pnas.0610690104
  26. Kim SY, Seo M, Kim Y, Lee YI, Oh JM, Cho EA, Kang JS, Juhnn YS. Stimulatory heterotrimeric GTP-binding protein inhibits hydrogen peroxide-induced apoptosis by repressing BAK induction in SH-SY5Y human neuroblastoma cells. J Biol Chem. 2008. 283: 1350-1361. https://doi.org/10.1074/jbc.M702344200
  27. Ko SH, Ryu GR, Kim S, Ahn YB, Yoon KH, Kaneto H, Ha H, Kim YS, Song KH. Inducible nitric oxide synthase-nitric oxide plays an important role in acute and severe hypoxic injury to pancreatic $\beta$-cells. Transplantation. 2008. 85: 323-330. https://doi.org/10.1097/TP.0b013e31816168f9
  28. Krinninger P, Brunner C, Ruiz PA, Schneider E, Marx N, Foryst- Ludwig A, Kintscher U, Haller D, Laumen H, Hauner H. Role of the adipocyte-specific NF-${\kappa}B$ activity in the regulation of IP-10 and T cell migration. Am J Physiol Endocrinol Metab. 2011. 300: E304-E311. https://doi.org/10.1152/ajpendo.00143.2010
  29. Lai Y BH, Hossain H, Bierhaus A, Chen C, Bretzel RG, Linn T. Activation of NF${\kappa}B$ dependent apoptotic pathway in pancreatic islet cells by hypoxia. Islets. 2009. 1: 19-25. https://doi.org/10.4161/isl.1.1.8530
  30. Lavie L. Sleep-disordered breathing and cerebrovascular disease: A mechanistic approach. Neurol Clin. 2005. 23: 1059-1075. https://doi.org/10.1016/j.ncl.2005.05.005
  31. Li C, Jackson RM. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol. 2002. 282: 227-241. https://doi.org/10.1152/ajpcell.00112.2001
  32. Liu Q, White LR, Clark SA, Heffner DJ, Winston BW, Tibbles LA, Muruve DA. Akt/protein kinase B activation by adenovirus vectors contributes to NF${\kappa}B$-dependent CXCL10 expression. J Virol. 2005. 79: 14507-14515. https://doi.org/10.1128/JVI.79.23.14507-14515.2005
  33. Liuwantara D, Elliot M, Smith MW, Yam AO, Walters SN, Marino E, McShea A, Grey ST. Nuclear factor-${\kappa}B$ regulates $\beta$-cell death: A critical role for A20 in $\beta$-cell protection. Diabetes. 2006. 55: 2491-2501. https://doi.org/10.2337/db06-0142
  34. Lu X, Masic A, Liu Q, Zhou Y. Regulation of influenza A virus induced CXCL-10 gene expression requires PI3K/Akt pathway and IRF3 transcription factor. Mol Immunol. 2011. 48: 1417-1423. https://doi.org/10.1016/j.molimm.2011.03.017
  35. Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM. p48/STAT1-$\alpha$-containing complexes play a predominant role in induction of IFN-$\gamma$-inducible protein, 10 kDa (IP-10) by IFN-$\gamma$ alone or in synergy with TNF-$\alpha$. J Immunol. 1998. 161: 4736-4744.
  36. Mokhtari D, Barbu A, Mehmeti I, Vercamer C, Welsh N. Overexpression of the nuclear factor-kappa B subunit c-Rel protects against human islet cell death in vitro. Am. J. Physiol- Endocrinol Metab. 2009. 297: E1067-E1077. https://doi.org/10.1152/ajpendo.00212.2009
  37. Moritz W, Meier F, Stroka DM, Giuliani M, Kugelmeier P, Nett PC, Lehmann R, Candinas D, Gassmann M, Weber M. Apoptosis in hypoxic human pancreatic islets correlates with HIF-1$\alpha$ expression. FASEB J. 2002. 16: 745-747.
  38. Ortis F, Pirot P, Naamane N, Kreins AY, Rasschaert J, Moore F, Theâtre E, Verhaeghe C, Magnusson NE, Chariot A, Orntoft TF, Eizirik DL. Induction of nuclear factor-${\kappa}B$ and its downstream genes by TNF-$\alpha$ and IL-1$\beta$ has a pro-apoptotic role in pancreatic $\beta$ cells. Diabetologia. 2008. 51: 1213-1225. https://doi.org/10.1007/s00125-008-0999-7
  39. Pacher P, Nivorozhkin A, Szabó C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev. 2006. 58: 87-114. https://doi.org/10.1124/pr.58.1.6
  40. Radhakrishnan SK, Kamalakaran S. Pro-apoptotic role of NF-${\kappa}B$: implications for cancer therapy. Biochim Biophys Acta. 2006. 1766: 53-62.
  41. Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases. Endocr Rev. 2007. 28: 492-520. https://doi.org/10.1210/er.2006-0044
  42. Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N, Sasaki T, Tsujioka K, Makino H, Kashihara N. NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Renal Physiol. 2005. 288: F1144-F1152. https://doi.org/10.1152/ajprenal.00221.2004
  43. Schulthess FT, Paroni F, Sauter NS, Shu L, Ribaux P, Haataja L, Strieter RM, Oberholzer J, King CC, Maedler K. CXCL10 impairs $\beta$-cell function and viability in diabetes through TLR4 signaling. Cell Metab. 2009. 9: 125-139. https://doi.org/10.1016/j.cmet.2009.01.003
  44. Stokes RA, Cheng K, Deters N, Lau SM, Hawthorne WJ, O'Connell PJ, Stolp J, Grey S, Loudovaris T, Kay TW, Thomas HE, Gonzalez FJ, Gunton JE. Hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$) potentiates $\beta$-cell survival after islet transplantation of human and mouse islets. Cell Transplant. 2013. 22: 253 -266. https://doi.org/10.3727/096368912X647180
  45. Tanaka S, Nishida Y, Aida K, Maruyama T, Shimada A, Suzuki M, Shimura H, Takizawa S, Takahashi M, Akiyama D, Arai- Yamashita S, Furuya F, Kawaguchi A, Kaneshige M, Katoh R, Endo T, Kobayashi T. Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated $\beta$-cell failure in fulminant type 1 diabetes. Diabetes. 2009. 58: 2285-2291. https://doi.org/10.2337/db09-0091
  46. Tu VC, Sun H, Bowden GT, Chen QM. Involvement of oxidants and AP-1 in angiotensin II-activated NFAT3 transcription factor. Am J Physiol Cell Physiol. 2007. 292: C1248-C1255. https://doi.org/10.1152/ajpcell.00624.2005
  47. Villagomez M, Bae SJ, Ogawa I, Takenaka M, and Katayama I. Tumour necrosis factor-$\alpha$ but not interferon-$\gamma$ is the main inducer of inducible protein-10 in skin fibroblasts from patients with atopic dermatitis. Brit J Dermatol. 2004. 150: 910-916. https://doi.org/10.1111/j.1365-2133.2004.05937.x
  48. Volchuk A, Ron D. The endoplasmic reticulum stress response in the pancreatic $\beta$-cell. Diabetes Obes Metabol. 2010. 12: 48-57. https://doi.org/10.1111/j.1463-1326.2010.01271.x
  49. Yeruva S, Ramadori G, Raddatz D. NF-${\kappa}B$-dependent synergistic regulation of CXCL10 gene expression by IL-1$\beta$ and IFN-$\gamma$ in human intestinal epithelial cell lines. Int J Colorectal Dis. 2008. 23: 305-317. https://doi.org/10.1007/s00384-007-0396-6
  50. Yuan H, Zhang X, Huang X, Lu Y, Tang W, Man Y, Wang S, Xi J, Li J. NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of $\beta$-cells via JNK, p38 MAPK and p53 pathways. PLoS ONE. 2010. 5: e15726. https://doi.org/10.1371/journal.pone.0015726
  51. Zheng X, Zheng X, Wang X, Ma Z, Sunkari VG, Botusan I, Takeda T, Bjorklund A, Inoue M, Catrina SB, Brismar K, Poellinger L, Pereira TS. Acute hypoxia induces apoptosis of pancreatic $\beta$-cell by activation of the unfolded protein response and upregulation of CHOP. Cell Death Dis. 2012. 3: e322. https://doi.org/10.1038/cddis.2012.66
  52. Zhou Y, Wang S, Ma J, Lei Z, Zhu H, Lei P, Yang Z, Zhang B, Yao X, Shi C, Sun L, Wu X, Ning Q, Shen G, Huang B. Hepatitis B virus protein X-induced expression of the CXC chemokine IP-10 is mediated through activation of NF-${\kappa}B$ and increases migration of leukocytes. J Biol Chem. 2010. 285: 12159-12168. https://doi.org/10.1074/jbc.M109.067629