• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Elucidation of the mechanism of TNF-induced reactive oxygen species-dependent cytotoxicity and development of its clinical application

Research Project

Project/Area Number 15390131
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionJuntendo University

Principal Investigator

NAKANO Hiroyasu  Juntendo Univ., Dept. Immunology, Assistant professor, 医学部, 講師 (70276476)

Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 2004: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2003: ¥6,100,000 (Direct Cost: ¥6,100,000)
KeywordsTNFα / NF-κB / reactive oxygen species(ROS) / JNK / necrosis / apoptosis / ER stress / oxidative stress / TNF / 活性酵素(ROS) / カスパーゼ / 抗酸化遺伝子 / eIF2α / NF-□B / 活性酸素 / MAPキナーゼ / TRAF / 抗酸化剤
Research Abstract

By using NF-κB activation-deficient cells, we demonstrate that TNFα stimulation leads to accumulation of reactive oxygen species(ROS), which is essential for prolonged mitogen-activated protein kinase(MAPK) activation and necrotic cell death. Moreover, microarray analysis shows that several antioxidant enzymes are induced by TNFα in an NF-κB-dependent manner. Collectively, a novel function of NF-κB is to suppress TNF-induced ROS accumulation by upregulating anti-oxidant enzymes.
Accumulation of unfolded proteins in the endoplasmic reticulum(ER) causes ER overload, resulting in ER stress. To cope with ER stress, mammalian cells trigger a specific response known as the unfolded protein response(UPR). By using murine fibrosarcoma L929 cells, in which tumor necrosis factor(TNF)α induces accumulation of reactive oxygen species(ROS) and cell death, we show that TNFαTh induces the UPR in a ROS-dependent fashion. In contrast to TNFα, oxidative stresses by H_2O_2 or arsenite only induce eIF2α phosphorylation, but not activation of PERK- or IRE1-dependent pathways, indicating the specificity of downstream signaling induced by various oxidative stresses. Conversely, the UPR induced by tunicamycin substantially suppresses TNFα-induced ROS accumulation and cell death. Collectively, some, but not all, oxidative stresses induce the UPR, and preemptive UPR counteracts TNFα-induced ROS accumulation.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (45 results)

All 2005 2004 2003 Other

All Journal Article (36 results) Publications (9 results)

  • [Journal Article] A revival of old players2005

    • Author(s)
      Nakano, H.
    • Journal Title

      EMBO Rep 6

      Pages: 126-127

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] A revival of old players.2005

    • Author(s)
      Nakano, H.
    • Journal Title

      EMBO Rep 6

      Pages: 126-127

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Signaling crosstalk between NF-κB and JNK2004

    • Author(s)
      Nakano, H.
    • Journal Title

      Trends Immunol 25

      Pages: 402-405

    • NAID

      10014313482

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] ROS mediate signaling crosstalk between NF-κB and JNK2004

    • Author(s)
      Pia, J.-H.et al.
    • Journal Title

      Gene Ther Mol Biol 8

      Pages: 163-174

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS2004

    • Author(s)
      Sasazuki, T. et al.
    • Journal Title

      Mol Immunol 41

      Pages: 547-551

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Transient and Selective NF-κB p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IκB Kinase β and Controls the Kinetics of p65 nuclear import2004

    • Author(s)
      Mattioli, I. et al.
    • Journal Title

      J Immunol 172

      Pages: 6336-6344

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NP-κB activation and transformation in resistant JB6 cells2004

    • Author(s)
      Hu, J.et al.
    • Journal Title

      Carcinogenesis 25

      Pages: 1991-2003

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TRAF Family Proteins Link PKR with NF-κB Activation2004

    • Author(s)
      Gil, J.et al.
    • Journal Title

      Mol Cell Biol 24

      Pages: 4502-4512

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] TNF Receptor-Associated Factor 5 Limits the Induction of Th2 Immune Responses2004

    • Author(s)
      So, T.et al.
    • Journal Title

      J Immunol 172

      Pages: 4292-4297

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Effects of PU.1-induced mouse calcium-calmodulin-dependent kinase I-like kinase (CKLiK) on apoptosis of murine erythroleukemia cells2004

    • Author(s)
      Yamada, T. et al.
    • Journal Title

      Exp Cell Res 294

      Pages: 39-50

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Signaling crosstalk between NF-κB and JNK.2004

    • Author(s)
      Nakano, H.
    • Journal Title

      Trends Immunol 25

      Pages: 402-405

    • NAID

      10014313482

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ROS mediate signaling crosstalk between NF-κB and JNK.2004

    • Author(s)
      Pia, J.-H., X.Xue, A.Nakajima, T.Sasazuki, K.Okumura, H.Nakano.
    • Journal Title

      Gene Ther Mol Biol 8

      Pages: 163-174

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS.2004

    • Author(s)
      Sasazuki, T., T.Okazaki, K.Tada, S.Sakon-Komazawa, M.Katano, M.Tanaka, H.Yagita, K.Okumura, N.Tominaga, Y.Hayashizaki, Y Okazaki, H.Nakano.
    • Journal Title

      Mol Immunol. 41

      Pages: 547-551

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transient and Selective NF-κB p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IκB Kinase β and Controls the Kinetics of p65 Nuclear Import.2004

    • Author(s)
      Mattioli, I., A.Sebald, C.Bucher, R.P.Charles, H.Nakano, T.Doi, M.Kracht, M.L.Schmitz.
    • Journal Title

      J Immunol 172

      Pages: 6336-6344

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-κB activation and transformation in resistant JB6 cells.2004

    • Author(s)
      Hu, J., H.Nakano, H.Sakurai, N.H.Colburn.
    • Journal Title

      Carcinogenesis 172

      Pages: 6336-6344

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TNF Receptor-Associated Factor 5 Limits the Induction of Th2 Immune Responses.2004

    • Author(s)
      So, T., S.Salek-Ardakani, H.Nakano, C.E Ware, M.Croft.
    • Journal Title

      J Immunol 25

      Pages: 1991-2003

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effects of PU.1-induced mouse calcium-calmodulin-dependent kinase I-like kinase (CKLiK) on apoptosis of murine erythroleukemia cells.2004

    • Author(s)
      Yamada, I., M.Suzuki, H.Satoh, F.Kihara-Negishi, H.Nakano, T.Gikawa.
    • Journal Title

      Exp Cell Res 172

      Pages: 4292-4297

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] NT-κB inhibits TNT-induced accumulation of ROS that mediate prolonged MAPK activation and necroti cell death.2004

    • Author(s)
      Sakon, S., X.Xue, M.Takekawa, T.Sasazuki, T.Okazaki, Y Kojima, J.H.Piao, H.Yagita, K.Okumura, T.Doi, H.Nakano.
    • Journal Title

      Embo J 294

      Pages: 39-50

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transient and Selective NF-κB p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by IκB Kinase β and Controls the Kinetics of p65 nuclear import2004

    • Author(s)
      Mattioli, I.et al.
    • Journal Title

      J Immunol 172

      Pages: 6336-6344

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-κB activation and transformation in resistant JB6 cells2004

    • Author(s)
      Hu, J.et al.
    • Journal Title

      Carcinogenesis 25

      Pages: 1991-2003

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effects of PU.1-induced mouse calcium-calmodulin-dependent kinase I-like kinase (CKLiK) on apoptosis of murine erythroleukemia cells2004

    • Author(s)
      Yamada, T.et al.
    • Journal Title

      Exp Cell Res 294

      Pages: 39-50

    • Related Report
      2004 Annual Research Report
  • [Journal Article] NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death2003

    • Author(s)
      Sakon, S. et al.
    • Journal Title

      EMBO J. 22

      Pages: 3898-3909

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation2003

    • Author(s)
      Hur, G.M.et al.
    • Journal Title

      Genes Dev 17

      Pages: 873-882

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Epstein-Barr virus latent membrane protein 1 activation of NF-κB through IRAK1 and TRAF62003

    • Author(s)
      Luftig, M. et al.
    • Journal Title

      Proc Natl Acad Sci U S A 100

      Pages: 15595-15600

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tumor Necrosis Factorα-induced IKK Phosphorylation of NF-κB p65 on Serine 536 Is Mediated through the TRAF2, TRAF5, and TAK1 Signaling Pathway2003

    • Author(s)
      Sakurai, H. et al.
    • Journal Title

      J Biol Chem 278

      Pages: 36916-36923

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TWEAK Induces NF-κB2 p100 Processing and Long Lasting NF-κB Activation2003

    • Author(s)
      Saitoh, T. et al.
    • Journal Title

      J Biol Chem 278

      Pages: 36005-36012

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The Role of Apoptosis Signal-regulating Kinase 1 in Lymphotoxin-β Receptor-mediated Cell Death2003

    • Author(s)
      Chen, M.C.et al.
    • Journal Title

      J Biol Chem 278

      Pages: 16073-16081

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TRAF5 functions in both RANKL- and TNFα-induced osteoclastogenesis2003

    • Author(s)
      Kanazawa, K. et al.
    • Journal Title

      J Bone Miner Res 18

      Pages: 443-450

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phosphorylation of serine 276 is essential for p65 NF-κB subunit-dependent cellular responses2003

    • Author(s)
      Okazaki, T. et al.
    • Journal Title

      Biochem Biophys Res Commun 300

      Pages: 807-812

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation.2003

    • Author(s)
      Hur, G.M., J.Lewis, Q.Yang, Y Lin, H.Nakano, S.Nedospasov, Z.G.Liu.
    • Journal Title

      Genes Dev 17

      Pages: 873-882

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Epstein-Barr virus latent membrane protein 1 activation of NF-κB through IRAK1 and TRAF6.2003

    • Author(s)
      Luftig, M., B.Prinarakis, T.Yasui, T.Tsichritzis, E.Cahir-McFarland, J.Inoue, H.Nakano, T.W.Mak, W.C.Yeh, X.Li, S.Akira, N.Suzuki, S.Suzuki, G.Mosialos, E.Kieff.
    • Journal Title

      Proc NatI Acad Sci U S A 100

      Pages: 15595-15600

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tumor Necrosis Factor α-induced IKK Phosphorylation of NF-κB p65 on Serine 536 Is Mediated through the TRAF2, TRAF5, and TAK1 Signaling Pathway.2003

    • Author(s)
      Sakurai, H., S.Suzuki, N.Kawasaki, H.Nakano, T.Okazaki, A.Chino, T.Doi, I.Saiki.
    • Journal Title

      J Biol Chem 278

      Pages: 36916-36923

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TWEAK Induces NF-κB2 p100 Processing and Long Lasting NF-κB Activation.2003

    • Author(s)
      Saitoh, T., M.Nakayama, H.Nakano, H.Yagita, N.Yamamoto, S.Yamaoka.
    • Journal Title

      J Biol Chem 278

      Pages: 36005-36012

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The Role of Apoptosis Signal regulating Kinase 1 in Lymphotoxin-β Receptor-mediated Cell Death.2003

    • Author(s)
      Chen, M.C., M.J.Hwang, YC.Chou, W.H.Chen, G.Cheng, H.Nakano, T.Y Luh, S.C.Mai, S.L.Hsieh.
    • Journal Title

      J Biol Chem 278

      Pages: 16073-16081

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TRAF5 functions in both RANKL- and TNFα-induced osteoclastogenesis.2003

    • Author(s)
      Kanazawa, K., Y Azuma, H.Nakano, A.Kudo.
    • Journal Title

      J Bone Miner Res 18

      Pages: 443-450

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phosphorylation of serine 276 is essential for p65 NV-κB subunit-dependent cellular responses.2003

    • Author(s)
      Okazaki, T., S.Sakon, T.Sasazuki, H.Sakurai, T.Doi, H.Yagita, K.Okumura, H.Nakano.
    • Journal Title

      Biochem Biophys Res Commun 300

      Pages: 807-812

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Sakon, S. et al.: "NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death"EMBO J.. 22. 3898-3909 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hur, G.M.et al.: "The death domain kinase RIP has an essential role in DNA damage-induced NF-κB activation"Genes Dev. 17. 873-882 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Luftig, M. et al.: "Epstein-Barr virus latent membrane protein 1 activation of NF-κB through IRAK1 and TRAF6"Proc Natl Acad Sci U S A. 100. 15595-15600 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sakurai, H. et al.: "Tumor Necrosis Factor α-induced IKK Phosphorylation of NF-κB p65 on Serine 536 Is Mediated through the TRAF2,TRAF5,and TAK1 Signaling Pathway"J Biol Chem. 278. 36916-36923 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Saitoh, T. et al.: "TWEAK Induces NF-κB2 p100 Processing and Long Lasting NF-□B Activation"J Biol Chem. 278. (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chen, M.C.et al.: "The Role of Apoptosis Signal-regulating Kinase 1 in Lymphotoxin-β Receptor-mediated Cell Death"J Biol Chem. 278. 16073-16081 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanazawa, K. et al.: "TRAF5 functions in both RANKL- and TNFα-induced osteoclastogenesis"J Bone Miner Res. 18. 443-450 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Okazaki, T. et al.: "Phosphorylation of serine 276 is essential for p65 NF-κB subunit-dependent cellular responses"Biochem Biophys Res Commun. 300. 807-812 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamada, T. et al.: "Effects of PU.1-induced mouse calcium calmodulin-dependent Kinase I-like kinase (CKLiK) on apoptosis of murine erythroleukemia cells"Exp Cell Res. (2003)

    • Related Report
      2003 Annual Research Report

URL: 

Published: 2003-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi