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  • The EMBO Journal (2003) 22, 3898 - 3909
  • doi:10.1093/emboj/cdg379

NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death

Sachiko Sakon1,2, Xin Xue1, Mutsuhiro Takekawa3,4, Tomonari Sasazuki1, Tatsuma Okazaki1, Yuko Kojima1, Jian-Hu Piao1, Hideo Yagita1, Ko Okumura1, Takahiro Doi5 and Hiroyasu Nakano1,2

  1. Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
  2. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Corporation (JST), 1-11-2 Yoyogi, Shibuya-ku, Tokyo 151-0053, Japan
  3. Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
  4. PRESTO, JST, Kawaguchi, Saitama 332-0012, Japan
  5. Subteam for BioResponse Integration, RIKEN (Institute of Physical and Chemical Research), BioResource Center, Tsukuba, Ibaraki 305-0074, Japan

Correspondence to:

Hiroyasu Nakano, E-mail: hnakano@med.juntendo.ac.jp

Received 16 January 2003; Accepted 6 June 2003; Revised 22 May 2003

NF-kappaB downregulates tumor necrosis factor (TNF)-induced c-Jun N-terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor-associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF-kappaB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen-activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild-type MEFs, indicating that TRAF-mediated NF-kappaB activation normally suppresses the TNF-induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death

  • Keywords:

    • MAPK,
    • NF-kappaB,
    • ROS,
    • TNF,
    • TRAF