An Essential Role for NF-κB in Preventing TNF-α-Induced Cell Death

Studies on mice deficient in nuclear factor kappa B (NF-κB) subunits have shown that this transcription factor is important for lymphocyte responses to antigens and cytokine-inducible gene expression. In particular, the RelA (p65) subunit is required for induction of tumor necrosis factor-α (TNF-α)-dependent genes. Treatment of RelA-deficient (RelA−/−) mouse fibroblasts and macrophages with TNF-α resulted in a significant reduction in viability, whereas RelA+/+ cells were unaffected. Cytotoxicity to both cell types was mediated by TNF receptor 1. Reintroduction of RelA into RelA−/− fibroblasts resulted in enhanced survival, demonstrating that the presence of RelA is required for protection from TNF-α. These results have implications for the treatment of inflammatory and proliferative diseases.

[1]  Seamus J. Martin,et al.  Suppression of TNF-α-Induced Apoptosis by NF-κB , 1996, Science.

[2]  E M Schwarz,et al.  Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. , 1995, Genes & development.

[3]  A. Baldwin,et al.  Role of Transcriptional Activation of IκBα in Mediation of Immunosuppression by Glucocorticoids , 1995, Science.

[4]  David Baltimore,et al.  Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB , 1995, Nature.

[5]  D. Goeddel,et al.  The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation , 1995, Cell.

[6]  J. Cleveland,et al.  Contenders in FasL/TNF death signaling , 1995, Cell.

[7]  David Baltimore,et al.  Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses , 1995, Cell.

[8]  P. Baeuerle,et al.  Function and activation of NF-kappa B in the immune system. , 1994, Annual review of immunology.

[9]  V. Dixit,et al.  The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity. , 1992, The Journal of biological chemistry.

[10]  N. Copeland,et al.  Molecular cloning and expression of the type 1 and type 2 murine receptors for tumor necrosis factor , 1991, Molecular and cellular biology.

[11]  E. Chen,et al.  Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Ruben,et al.  Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. , 1991, Science.

[13]  G. Nolan,et al.  Cloning of the p50 DNA binding subunit of NF-κB: Homology to rel and dorsal , 1990, Cell.

[14]  S. Natori,et al.  Expression of tumor necrosis factor at a specific developmental stage of mouse embryos. , 1989, Developmental biology.

[15]  G. Wong,et al.  Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor , 1989, Cell.

[16]  D. Goeddel,et al.  Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism , 1988, Science.

[17]  W. Fiers,et al.  The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity , 1988, The Journal of experimental medicine.

[18]  J. Gamble,et al.  Stimulation of neutrophils by tumor necrosis factor. , 1986, Journal of immunology.

[19]  J. Gamble,et al.  Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[20]  B. Aggarwal,et al.  Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. , 1985, Science.

[21]  R L Kassel,et al.  An endotoxin-induced serum factor that causes necrosis of tumors. , 1975, Proceedings of the National Academy of Sciences of the United States of America.