TNF-induced Mechanisms for IL6 Gene Induction

  • Guy Haegeman
  • Walter Fiers
Part of the NATO ASI Series book series (volume 92)


Tumor Necrosis Factor (TNF) is a pleiotropic cytokine, originally detected and at present still mostly important because of its cytostatic/cytotoxic potential towards several transformed cell lines (Fiers, 1993). One of the prototypic cell lines for studying the cell killing effects of TNF is the mouse fibrosarcoma line L929. TNF treatment of L929 cells not only leads to cellular toxicity, but also results in the induction of several genes, among which the gene coding for Interleukin-6 (IL6). However, the mechanism of both TNF effects, i.e. gene induction and cell killing, is not yet fully understood, nor are the corresponding signaling intermediates at present known in great detail. In an effort to elucidate the cellular processes, which take place following TNF induction, numerous studies are being pursued regarding different levels of the signaling path way (s), i.e. from intracellular interactions with the membrane bound receptor, down to the actual site of action. In this paper, we will briefly review and mainly focus oil the molecular mechanisms for activation of the IL6 gene promoter in response to TNF.


L929 Cell NFKB Activation Transcription Factor NFKB Cell Killing Effect Tumor Necrosis Factor Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T (1990) A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J 9:1897–1906PubMedGoogle Scholar
  2. Baeuerle PA, Baltimore D (1989) A 65-kD subunit of active NF-icB is required for inhibition of NF-IDB by I/cB. Genes Development 3:1689–1698PubMedCrossRefGoogle Scholar
  3. Baeuerle PA, Baltimore D (1988) IdB: A specific inhibitor of the NF-JCB transcription factor. Science 242:540–546PubMedCrossRefGoogle Scholar
  4. Baeuerle PA, Henkel T (1994) Function and activation of NF-JCB in the immune system. Annu Rev Immunol 12:141–179PubMedCrossRefGoogle Scholar
  5. Beg AA, Finco TS, Nantermet PV, Baldwin Jr AS (1993) Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of IicBa: A mechanism for NF-JCB activation. Mol Cell Biol 13:3301–3310PubMedGoogle Scholar
  6. Boone E, Fiers W, Haegeman G (1995) TNF-mediated gene induction involves protein kinase C activity and tyrosine kinase phosphorylation. In preparation.Google Scholar
  7. Brown K, Park S, Kanno T, Franzoso G, Siebenlist U (1993) Mutual regulation of the transcriptional activator NF-icB and its inhibitor, I/cB-a. Proc Natl Acad Sci USA 90:2532–2536PubMedCrossRefGoogle Scholar
  8. Cordle SR, Donald R, Read MA, Hawiger J (1993) Lipopolysaccharide induces phosphorylation of MAD3 and activation of c-Rel and related NF-JCB proteins in human monocytic THP-1 cells. J Biol Chem 268:11803–11810PubMedGoogle Scholar
  9. Dendorfer U, Oettgen P, Libermann TA (1994) Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Ceil Biol 14:4443–4454Google Scholar
  10. Diaz-Meco M, Dominguez I, Sanz L, Dent P, Lozano J, Municio MM, Berra E, Hay RT, Sturgill TW, Moscat J (1994) fPKC induces phosphorylation and inactivation of IjcB-a in vitro. EMBO J 13:2842–2848Google Scholar
  11. Fiers W (1993) Tumour necrosis factor. In The Natural Immune System: Humoral Factors (Sim E, ed), 65–119. IRL Press OxfordGoogle Scholar
  12. Gaiter D, Mihm S, Drôge W (1994) Distinct effects of glutathione disulphide on the nuclear transcription factors kB and the activator protein-1. Eur J Biochem 221:639–648CrossRefGoogle Scholar
  13. Henkel T, Machleidt T, Alkalay I, Krônke M, Ben-Neriah Y, Baeuerle PA (1993) Rapid proteolysis of IicB-ce is necessary for activation of transcription factor NF-kB. Nature 365:182–185PubMedCrossRefGoogle Scholar
  14. Israël N, Gougerot-Pocidalo M-A, Aillet F, Virelizier J-L (1992) Redox status of cells influences constitutive or induced NF-icB translocation and HIV long terminal repeat activity in human T and monocytic cell lines. J Immunol 149:3386–3393PubMedGoogle Scholar
  15. Isshiki H, Akira S, Tanabe O, Nakajima T, Shimamoto T, Hirano T, Kishimoto T (1990) Constitutive and interleukin-1 (IL-l)-inducible factors interact with the II - 1-responsive element in the IL-6 gene. Mol Cell Biol 10:2757–2764PubMedGoogle Scholar
  16. Kanno T, Brown K, Franzoso G, Siebenlist U (1994) Kinetic analysis of human T-cell leukemia virus type I Tax-mediated activation of NF-JCB. Mol Cell Biol 14:6443–6451Google Scholar
  17. Klampfer L, Lee TH, Hsu W, Vilcek J, Chen-Kiang S (1994) NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1. Mol Cell Biol 14:6561–6569PubMedGoogle Scholar
  18. Koong AC, Chen EY, Giaccla AJ (1994) Hypoxia causes the activation of nuclear factor JCB through the phosphorylation of IICBA on tyrosine residues. Cancer Res 54:1425–1430PubMedGoogle Scholar
  19. LeClair KP, Blanar MA, Sharp PA (1992) The p50 subunit of NF-KB associates with the NF-IL6 transcription factor. Proc Natl Acad Sci USA 89:8145–8149CrossRefGoogle Scholar
  20. Libermann TA, Baltimore D (1990) Activation of interleukin-6 gene expression through the NF-kB transcription factor. Mol Cell Biol 10:2327–2334PubMedGoogle Scholar
  21. Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993) Transcription factors NF-IL6 and NF-KB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci USA 90:10193–10197PubMedCrossRefGoogle Scholar
  22. Meichle A, Schütze S, Hensel G, Brunsing D, Krönke M (1990) Protein kinase C-independent activation of nuclear factor KB by tumor necrosis factor. J Biol Chem 265:8339–8343PubMedGoogle Scholar
  23. Mellits KH, Hay RT, Goodbourn S (1993) Proteolytic degradation of MAD3 (UBA) and enhanced processing of the NF-kB precursor pi05 are obligatory steps in the activation of NF-KB. Nucleic Acids Res 21:5059–5066PubMedCrossRefGoogle Scholar
  24. Mukaida N, Mahe Y, Matsushima K (1990) Cooperative interaction of nuclear factor-KB- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J Biol Chem 265:21128–21133PubMedGoogle Scholar
  25. Naumann M, Scheidereit C (1994) Activation of NF-icB in vivo is regulated by multiple phosphorylations. EMBO J 13:4597–4607PubMedGoogle Scholar
  26. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin-proteasome pathway is required for processing the NF-icBl precursor protein and the activation of NF-JCB. Cell 78:773–785PubMedCrossRefGoogle Scholar
  27. Patestos NP, Haegeman G, Vandevoorde V, Fiers W (1993) Activation of the nuclear factor #cB is not sufficient for regulation of tumor necrosis factor-induced interleukin-6 gene expression. Biochimie 75:1007–1018PubMedCrossRefGoogle Scholar
  28. Ray A, Prefontaine KE (1994) Physical association and functional antagonism between the p65 subunit of transcription factor NF-JCB and the glucocorticoid receptor. Proc Natl Acad Sci USA 91:752–756PubMedCrossRefGoogle Scholar
  29. Renard P, Zachary M-D, Bougelet C, Remacle J, Raes M (1994) Modulation of human cultured fibroblasts cell redox potential: Effects on the transcriptional factor NF/cB activated by IL-1. International Summer School on Molecular Mechanisms of Transcellular Signaling: From the Membrane to the Gene. Spetsai, Poster Abstracts, 65 Rice NR, Ernst MK (1993) In vivo control of NF-/cB activation by IicBa. EMBO J 12:4685–4695Google Scholar
  30. Schenk H, Klein M, Erdbrügger W, Dröge W, Schulze-Osthoff K (1994) Distinct effects of thioredoxin and antioxidants on the activation of transcription factors NF-KB and AP-1. Proc Natl Acad Sci USA 91:1672–1676PubMedCrossRefGoogle Scholar
  31. Schreck R, Meier B, Männel DN, Dröge W, Baeuerle PA (1992) Dithiocarbamates as potent inhibitors of nuclear factor #cB activation in intact cells. J Exp Med 175:1181–1194PubMedCrossRefGoogle Scholar
  32. Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-icB transcription factor and HIV-1. EMBO J 10:2247–2258PubMedGoogle Scholar
  33. Schulze-Osthoff K, Beyaert R, Vandevoorde V, Haegeman G, Fiers W (1993) Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. EMBO J 12:3095–3104PubMedGoogle Scholar
  34. Schütze S, Potthoff K, Machleidt T, Berkovic D, Wiegmann K, Krönke M (1992) TNF activates NF-KB by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 71:765–776PubMedCrossRefGoogle Scholar
  35. Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716PubMedCrossRefGoogle Scholar
  36. Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K (1990) Involvement of a NF-icB-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol 10:561–568PubMedGoogle Scholar
  37. Staal FJT, Roederer M, Herzenberg LA, Herzenberg LA (1990) Intracellular thiols regulate activation of nuclear factor KB and transcription of human immunodeficiency virus. Proc Natl Acad Sci USA 87:9943–9947PubMedCrossRefGoogle Scholar
  38. Stein B, Cogswell PC, Baldwin Jr AS (1993) Functional and physical associations between NF-KB and C/EBP family members: A Rel domain-bZIP interaction. Mol Cell Biol 13:3964–3974PubMedGoogle Scholar
  39. Sun S-C, Elwood J, Beraud C, Greene WC (1994) Human T-cell leukemia virus type I Tax activation of NF-icB/Rei involves phosphorylation and degradation of IicBa and RelA (p65)-mediated induction of the c-rel gene. Mol Cell Biol 14:7377–7384PubMedGoogle Scholar
  40. Sun S-C, Ganchi PA, Ballard DW, Greene WC (1993) NF-JCB controls expression of inhibitor IkBα: Evidence for an inducible autoregulatory pathway. Science 259:1912–1915PubMedCrossRefGoogle Scholar
  41. Suzuki YJ, Packer L (1993) Inhibition of NF-kB activation by vitamin E derivatives. Biochem Biophys Res Commun 193:277–283CrossRefGoogle Scholar
  42. Tanabe O, Akira S, Kamiya T, Wong GG, Hirano T, Kishimoto T (1988) Genomic structure of the murine IL-6 gene. High degree conservation of potential regulatory sequences between mouse and human. J Immunol 141:3875–3881PubMedGoogle Scholar
  43. Vanden Berghe W, Haegeman G, Fiers W (1993) Studies on the inducibility of the IL6 promoter using a reporter gene construction. Arch Intern Physiol Biochim Biophys 101:B35CrossRefGoogle Scholar
  44. Vandevoorde V, Haegeman G, Fiers W (1992) TNF-mediated IL6 gene expression and cytotoxicity are co-inducible in TNF-resistant L929 cells. FEBS Lett 302:235–238Google Scholar
  45. Vandevoorde V, Haegeman G, Fiers W (1991) Tumor necrosis factor-induced interleukin-6 expression and cytotoxicity follow a common signal transduction pathway in L929 cells. Biochem Biophys Res Commun 178:993–1001PubMedCrossRefGoogle Scholar
  46. Wiegmann K, Schütze S, Machleidt T, Witte D, Krönke M (1994) Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 78:1005–1015PubMedCrossRefGoogle Scholar
  47. Zhang Y, Broser M, Rom WN (1994) Activation of the interleukin 6 gene by Mycobacterium tuberculosis or lipopolysaccharide is mediated by nuclear factors NF-IL6 and NF-KB. Proc Natl Acad Sci USA 91:2225–2229PubMedCrossRefGoogle Scholar
  48. Zhang Y, Lin J-X, Vilcek J (1990) Interleukin-6 induction by tumor necrosis factor and interleukin-1 in human fibroblasts involves activation of a nuclear factor binding to a kB-like sequence. Mol Cell Biol 10:3818–3823PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • Guy Haegeman
    • 1
  • Walter Fiers
    • 1
  1. 1.Laboratorium voor Moleculaire BiologieGentBelgium

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