JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species

  1. Juan-Jose Ventura1,
  2. Patricia Cogswell2,
  3. Richard A. Flavell3,
  4. Albert S. Baldwin, Jr.2, and
  5. Roger J. Davis1,4
  1. 1Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; 2Lineberger Cancer Research Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 3Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA

Abstract

The c-Jun NH2-terminal kinase (JNK) has been implicated in both cell death and survival responses to different stimuli. Here we reexamine the function of JNK in tumor necrosis factor (TNF)-stimulated cell death using fibroblasts isolated from wild-type, Mkk4-/- Mkk7-/-, and Jnk1-/- Jnk2-/- mice. We demonstrate that JNK can act to suppress TNF-stimulated apoptosis. However, we find that JNK can also potentiate TNF-stimulated necrosis by increasing the production of reactive oxygen species (ROS). Together, these data indicate that JNK can shift the balance of TNF-stimulated cell death from apoptosis to necrosis. Increased necrosis may represent a contributing factor in stress-induced inflammatory responses mediated by JNK.

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Footnotes

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1223004.

  • ↵4 Corresponding author. E-MAIL Roger.Davis{at}Umassmed.Edu; FAX (508) 856-3210.

    • Accepted September 20, 2004.
    • Received May 18, 2004.
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This Article

  1. Published in Advance November 15, 2004, doi: 10.1101/gad.1223004 Genes & Dev. 18: 2905-2915 Cold Spring Harbor Laboratory Press

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