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  • The EMBO Journal (2003) 22, 3356 - 3366
  • doi:10.1093/emboj/cdg332

Evidence that reactive oxygen species do not mediate NF-kappaB activation

Makio Hayakawa1, Hiroshi Miyashita1, Isao Sakamoto1, Masatoshi Kitagawa2, Hirofumi Tanaka3, Hideyo Yasuda3, Michael Karin4 and Kiyomi Kikugawa1

  1. School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Tokyo 192-0392, Japan
  2. Department of Biochemistry 1, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan
  3. School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Tokyo 192-0392, Japan
  4. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

Correspondence to:

Kiyomi Kikugawa, E-mail: kikugawa@ps.toyaku.ac.jp

Received 6 December 2002; Accepted 15 May 2003; Revised 28 April 2003

It has been postulated that reactive oxygen species (ROS) may act as second messengers leading to nuclear factor (NF)-kappaB activation. This hypothesis is mainly based on the findings that N-acetyl-L-cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), compounds recognized as potential antioxidants, can inhibit NF-kappaB activation in a wide variety of cell types. Here we reveal that both NAC and PDTC inhibit NF-kappaB activation independently of antioxidative function. NAC selectively blocks tumor necrosis factor (TNF)-induced signaling by lowering the affinity of receptor to TNF. PDTC inhibits the IkappaB–ubiquitin ligase activity in the cell-free system where extracellular stimuli-regulated ROS production does not occur. Furthermore, we present evidence that endogenous ROS produced through Rac/NADPH oxidase do not mediate NF-kappaB signaling, but instead lower the magnitude of its activation.

  • Keywords:

    • NAC,
    • NF-kappaB,
    • PDTC,
    • reactive oxygen species,
    • redox