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  • Review Article
  • Published:

NF-κB regulation in the immune system

An Erratum to this article was published on 01 December 2002

Key Points

  • Nuclear factor-κB (NF-κB) has a seminal role in immunity. Aberrant NF-κB activity is associated with various inflammatory diseases.

  • NF-κB activation is controlled by its cellular localization through its association with inhibitor of NF-κB (IκB) proteins. This is achieved by a dynamic shuttling of latent NF-κB–IκBα complexes between the cytoplasm and nucleus.

  • Most of the pathways that result in NF-κB activation converge on activating the IκB kinase (IKK) complex. Subsequently, IKK phosphorylates IκB, resulting in the degradation of IκB and the release of NF-κB, which translocates to the nucleus to bind specific DNA sequences.

  • Additional signalling pathways are required for NF-κB transactivation by modification of its phosphorylation sites.

  • NF-κB pathways provide many targets for developing specific drugs to treat inflammatory diseases.

Abstract

The nuclear factor-κB (NF-κB)/REL family of transcription factors has a central role in coordinating the expression of a wide variety of genes that control immune responses. There has been intense scientific activity in the NF-κB field owing to the involvement of these factors in the activation and regulation of key molecules that are associated with diseases ranging from inflammation to cancer. In this review, we focus on our current understanding of NF-κB regulation and its role in the immune system and inflammatory diseases. We also discuss the role of NF-κB proteins as potential therapeutic targets in clinical applications.

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Figure 1: Mammalian NF-κB- and IκB-family members.
Figure 2: NF-κB activation pathways.
Figure 3: A model of how NF-κB phosphorylation regulates its transactivation function.

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References

  1. Verma, I. M., Stevenson, J. K., Schwarz, E. M., Van Antwerp, D. & Miyamoto, S. Rel/NF-κB/IκB family: intimate tales of association and dissociation. Genes Dev. 9, 2723–2735 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. May, M. J. & Ghosh, S. Rel/NF-κB and IκB proteins: an overview. Semin. Cancer Biol. 8, 63–73 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Silverman, N. & Maniatis, T. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15, 2321–2342 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Gerondakis, S., Grossmann, M., Nakamura, Y., Pohl, T. & Grumont, R. Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts. Oncogene 18, 6888–6895 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Dechend, R. et al. The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators. Oncogene 18, 3316–3323 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Huxford, T., Huang, D. B., Malek, S. & Ghosh, G. The crystal structure of the IκBα/NF-κB complex reveals mechanisms of NF-κB inactivation. Cell 95, 759–770 (1998).The 2.3 Å crystal structure of IκBα in complex with the NF-κB p50–p65 heterodimer indicates the mechanisms of the inhibitory activity of IκBα.

    Article  CAS  PubMed  Google Scholar 

  8. Birbach, A. et al. Signaling molecules of the NF-κB pathway shuttle constitutively between cytoplasm and nucleus. J. Biol. Chem. 277, 10842–10851 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Huang, T. T. & Miyamoto, S. Postrepression activation of NF-κB requires the amino-terminal nuclear export signal specific to IκBα. Mol. Cell. Biol. 21, 4737–4747 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Johnson, C., Van Antwerp, D. & Hope, T. J. An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IκBα. EMBO J. 18, 6682–6693 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang, T. T., Kudo, N., Yoshida, M. & Miyamoto, S. A nuclear export signal in the N-terminal regulatory domain of IκBα controls cytoplasmic localization of inactive NF-κB/IκBα complexes. Proc. Natl Acad. Sci. USA 97, 1014–1019 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Malek, S., Chen, Y., Huxford, T. & Ghosh, G. IκBβ, but not IκBα, functions as a classical cytoplasmic inhibitor of NF-κB dimers by masking both NF-κB nuclear localization sequences in resting cells. J. Biol. Chem. 276, 45225–45235 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Lee, S. H. & Hannink, M. Characterization of the nuclear import and export functions of IκBα. J. Biol. Chem. 277, 23358–23366 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Tam, W. F. & Sen, R. IκB family members function by different mechanisms. J. Biol. Chem. 276, 7701–7704 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Fenwick, C. et al. A subclass of Ras proteins that regulate the degradation of IκB. Science 287, 869–873 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Beg, A. A., Sha, W. C., Bronson, R. T. & Baltimore, D. Constitutive NF-κB activation, enhanced granulopoiesis and neonatal lethality in IκBα-deficient mice. Genes Dev. 9, 2736–2746 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Cheng, J. D., Ryseck, R. P., Attar, R. M., Dambach, D. & Bravo, R. Functional redundancy of the nuclear factor-κB inhibitors IκBα and IκBβ. J. Exp. Med. 188, 1055–1062 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Imler, J. L. & Hoffmann, J. A. Toll and Toll-like proteins: an ancient family of receptors signaling infection. Rev. Immunogenet. 2, 294–304 (2000).

    CAS  PubMed  Google Scholar 

  19. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675–680 (2001).

    Article  CAS  Google Scholar 

  20. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Kelliher, M. A. et al. The death-domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Yang, J. et al. The essential role of MEKK3 in TNF-induced NF-κB activation. Nature Immunol. 2, 620–624 (2001).

    Article  CAS  Google Scholar 

  23. Arendt, C. W., Albrecht, B., Soos, T. J. & Littman, D. R. Protein kinase Cθ: signaling from the center of the T-cell synapse. Curr. Opin. Immunol. 14, 323–330 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Sun, Z. et al. PKC-θ is required for TCR-induced NF-κB activation in mature but not immature T lymphocytes. Nature 404, 402–407 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Ruland, J. et al. Bcl10 is a positive regulator of antigen-receptor-induced activation of NF-κB and neural-tube closure. Cell 104, 33–42 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. McAllister-Lucas, L. M. et al. Bimp1, a MAGUK family member linking protein kinase C activation to Bcl10-mediated NF-κB induction. J. Biol. Chem. 276, 30589–30597 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Ben-Neriah, Y. Regulatory functions of ubiquitination in the immune system. Nature Immunol. 3, 20–26 (2002).

    Article  CAS  Google Scholar 

  29. Li, Q., Estepa, G., Memet, S., Israel, A. & Verma, I. M. Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev. 14, 1729–1733 (2000).The absence of IKK1 and IKK2 completely blocks IκB degradation and NF-κB activation, at least in mouse embryonic fibroblasts, which indicates that IKK1 and IKK2 are key IκB kinases for diverse NF-κB signalling pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Rudolph, D. et al. Severe liver degeneration and lack of NF-κB activation in NEMO/IKKκ-deficient mice. Genes Dev. 14, 854–862 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. & Verma, I. M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321–325 (1999).The use of IKK2-deficient mice shows that IKK2 is an important IκB kinase for the degradation of IκB and NF-κB activation.

    Article  CAS  PubMed  Google Scholar 

  32. Hu, Y. et al. IKKα controls formation of the epidermis independently of NF-κB. Nature 410, 710–714 (2001).This study shows that the function of IKK1 in keratinocyte differentiation is independent of its kinase activity and NF-κB activation.

    Article  CAS  PubMed  Google Scholar 

  33. Li, Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322–1328 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sizemore, N., Lerner, N., Dombrowski, N., Sakurai, H. & Stark, G. R. Distinct roles of the IκB kinase α and β subunits in liberating nuclear factor-κB (NF-κB) from IκB and in phosphorylating the p65 subunit of NF-κB. J. Biol. Chem. 277, 3863–3869 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Cao, Y. et al. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary-gland development. Cell 107, 763–775 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Xiao, G., Harhaj, E. W. & Sun, S. C. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol. Cell 7, 401–409 (2001).The processing of p100 to generate p52 is inhibited in NIK-deficient cells, which indicates that NIK is necessary for p100 processing.

    Article  CAS  PubMed  Google Scholar 

  38. Smahi, A. et al. Genomic rearrangement in NEMO impairs NF-κB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature 405, 466–472 (2000).The authors show that most cases of incontinentia pigmenti are due to mutations of the NEMO gene and that a new genomic rearrangement accounts for 80% of new mutations. As a consequence, NF-κB activation is defective in cells from patients who have incontinentia pigmenti.

    Article  CAS  PubMed  Google Scholar 

  39. Doffinger, R. et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-κB signaling. Nature Genet. 27, 277–285 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Schmidt-Supprian, M. et al. NEMO/IKKα-deficient mice model incontinentia pigmenti. Mol. Cell 5, 981–992 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Makris, C. et al. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5, 969–979 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Devin, A. et al. The α and β subunits of IκB kinase (IKK) mediate TRAF2-dependent IKK recruitment to tumor-necrosis factor (TNF) receptor 1 in response to TNF. Mol. Cell. Biol. 21, 3986–3994 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Poyet, J. L. et al. Activation of the IκB kinases by RIP via IKKγ/NEMO-mediated oligomerization. J. Biol. Chem. 275, 37966–37977 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Inohara, N. et al. An induced proximity model for NF-κB activation in the Nod1/RICK and RIP signaling pathways. J. Biol. Chem. 275, 27823–27831 (2000).

    CAS  PubMed  Google Scholar 

  45. Tarassishin, L. & Horwitz, M. S. Sites on FIP-3 (NEMO/IKKγ) essential for its phosphorylation and NF-κB modulating activity. Biochem. Biophys. Res. Commun. 285, 555–560 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Carter, R. S., Geyer, B. C., Xie, M., Acevedo-Suarez, C. A. & Ballard, D. W. Persistent activation of NF-κB by the tax transforming protein involves chronic phosphorylation of IκB kinase subunits IKKβ and IKKγ. J. Biol. Chem. 276, 24445–24448 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Chen, G., Cao, P. & Goeddel, D. V. TNF-induced recruitment and activation of the IKK complex require Cdc37 and Hsp90. Mol. Cell 9, 401–410 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Peters, R. T. & Maniatis, T. A new family of IKK-related kinases may function as IκB kinase kinases. Biochim. Biophys. Acta 2, M57–M62 (2001).

    Google Scholar 

  49. Kishore, N. et al. IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme, IKK-2. Comparative analysis of rhIKK-i, rhTBK-1 and rhIKK-2. J. Biol. Chem. 277, 13840–13847 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Bonnard, M. et al. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-κB-dependent gene transcription. EMBO J. 19, 4976–4985 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yujiri, T. et al. MEK kinase 1 gene disruption alters cell migration and c-Jun NH2-terminal kinase regulation but does not cause a measurable defect in NF-κB activation. Proc. Natl Acad. Sci. USA 97, 7272–7277 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xia, Y. et al. MEK kinase 1 is critically required for c-Jun N-terminal kinase activation by proinflammatory stimuli and growth factor-induced cell migration. Proc. Natl Acad. Sci. USA 97, 5243–5248 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yin, L. et al. Defective lymphotoxin-β receptor-induced NF-κB transcriptional activity in NIK-deficient mice. Science 291, 2162–2165 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Tojima, Y. et al. NAK is an IκB kinase-activating kinase. Nature 404, 778–782 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Dumitru, C. D. et al. TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103, 1071–1083 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Leitges, M. et al. Targeted disruption of the ζPKC gene results in the impairment of the NF-κB pathway. Mol. Cell 8, 771–780 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Zhong, H., Voll, R. E. & Ghosh, S. Phosphorylation of NF-κB p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol. Cell 1, 661–671 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, D., Westerheide, S. D., Hanson, J. L. & Baldwin, A. S. Jr. Tumor-necrosis factor-α-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J. Biol. Chem. 275, 32592–32597 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Sakurai, H., Chiba, H., Miyoshi, H., Sugita, T. & Toriumi, W. IκB kinases phosphorylate NF-κB p65 subunit on serine 536 in the transactivation domain. J. Biol. Chem. 274, 30353–30356 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Hoeflich, K. P. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Koul, D., Yao, Y., Abbruzzese, J. L., Yung, W. K. & Reddy, S. A. Tumor suppressor MMAC/PTEN inhibits cytokine-induced NFκB activation without interfering with the IκB degradation pathway. J. Biol. Chem. 276, 11402–11408 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Eberharter, A. & Becker, P. B. Histone acetylation: a switch between repressive and permissive chromatin: second in review series on chromatin dynamics. EMBO Rep. 3, 224–229 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee, S. K., Kim, J. H., Lee, Y. C., Cheong, J. & Lee, J. W. Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-κB and serum response factor. J. Biol. Chem. 275, 12470–12474 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Ito, K., Barnes, P. J. & Adcock, I. M. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1β-induced histone H4 acetylation on lysines 8 and 12. Mol. Cell Biol. 20, 6891–6903 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ashburner, B. P., Westerheide, S. D. & Baldwin, A. S. Jr. The p65 (RelA) subunit of NF-κB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol. Cell. Biol. 21, 7065–7077 (2001).This paper shows that the inhibition of HDAC activity with trichostatin A results in an increase in both basal and induced expression of an integrated NF-κB-dependent reporter gene and that p65 associates directly with HDAC1 and HDAC2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen, L., Fischle, W., Verdin, E. & Greene, W. C. Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293, 1653–1657 (2001).A demonstration that p65 is subject to inducible acetylation and that the acetylation status affects its binding affinity for IκBα. The authors propose that deacetylation of p65 by HDAC3 acts as an intranuclear molecular switch that both controls the duration of the NF-κB transcriptional response and contributes to the replenishment of the depleted cytoplasmic pool of latent NF-κB–IκBα complexes.

    Article  CAS  Google Scholar 

  67. Zhong, H., May, M. J., Jimi, E. & Ghosh, S. The phosphorylation status of nuclear NF-κB determines its association with CBP/p300 or HDAC-1. Mol. Cell 9, 625–636 (2002).This study shows that induced specific phosphorylation of p65 determines whether it associates with either CBP or HDAC1, which ensures that only p65 that enters the nucleus from cytoplasmic NF-κB–IκB complexes can activate transcription.

    Article  CAS  PubMed  Google Scholar 

  68. Furia, B. et al. Enhancement of nuclear factor-κB acetylation by coactivator p300 and HIV-1 Tat proteins. J. Biol. Chem. 277, 4973–4980 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Perkins, N. D. The Rel/NF-κB family: friend and foe. Trends Biochem. Sci. 25, 434–440 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Gerondakis, S., Grumont, R., Rourke, I. & Grossmann, M. The regulation and roles of Rel/NF-κB transcription factors during lymphocyte activation. Curr. Opin. Immunol. 10, 353–359 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Horwitz, B. H., Scott, M. L., Cherry, S. R., Bronson, R. T. & Baltimore, D. Failure of lymphopoiesis after adoptive transfer of NF-κB-deficient fetal liver cells. Immunity 6, 765–772 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Senftleben, U., Li, Z. W., Baud, V. & Karin, M. IKKβ is essential for protecting T cells from TNFα-induced apoptosis. Immunity 14, 217–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Boothby, M. R., Mora, A. L., Scherer, D. C., Brockman, J. A. & Ballard, D. W. Perturbation of the T lymphocyte lineage in transgenic mice expressing a constitutive repressor of nuclear factor (NF-κB). J. Exp. Med. 185, 1897–1907 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Caamano, J. & Hunter, C. A. NF-κB family of transcription factors: central regulators of innate and adaptive immune functions. Clin. Microbiol. Rev. 15, 414–429 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ferreira, V. et al. In vivo inhibition of NF-κB in T-lineage cells leads to a dramatic decrease in cell proliferation and cytokine production and to increased cell apoptosis in response to mitogenic stimuli, but not to abnormal thymopoiesis. J. Immunol. 162, 6442–6450 (1999).

    CAS  PubMed  Google Scholar 

  76. Mora, A. L., Youn, J., Keegan, A. & Boothby, M. R. NF-κB/Rel participation in the lymphokine-dependent proliferation of T lymphoid cells. J. Immunol. 166, 2218–2227 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Ouaaz, F., Li, M. & Beg, A. A. A critical role for the RelA subunit of nuclear factor-κB in regulation of multiple immmune-response genes and in Fas-induced cell death. J. Exp. Med. 189, 999–1004 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kojima, H. et al. An essential role for NF-κB in IL-18-induced IFN-γ expression in KG-1 cells. J. Immunol. 162, 5063–5069 (1999).

    CAS  PubMed  Google Scholar 

  79. Aronica, M. A. et al. Preferential role for NF-κB/Rel signaling in the type 1 but not type 2 T-cell-dependent immune response in vivo. J. Immunol. 163, 5116–5124 (1999).

    CAS  PubMed  Google Scholar 

  80. Aune, T. M., Mora, A. L., Kim, S., Boothby, M. R. & Lichtman, A. H. Costimulation reverses the defect in IL-2 but not effector cytokine production by T cells with impaired IκBα degradation. J. Immunol. 162, 5805–5812 (1999).

    CAS  PubMed  Google Scholar 

  81. Franzoso, G. et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 11, 3482–3496 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kaisho, T. et al. IκB kinase α is essential for mature B-cell development and function. J. Exp. Med. 193, 417–426 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hettmann, T., DiDonato, J., Karin, M. & Leiden, J. M. An essential role for nuclear factor-κB in promoting double-positive thymocyte apoptosis. J. Exp. Med. 189, 145–158 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Baeuerle, P. A. & Baichwal, V. R. NF-κB as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv. Immunol. 65, 111–137 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Tak, P. P. & Firestein, G. S. NF-κB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yang, L. et al. Essential role of nuclear factor κB in the induction of eosinophilia in allergic airway inflammation. J. Exp. Med. 188, 1739–1750 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Donovan, C. E. et al. NF-κB/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation. J. Immunol. 163, 6827–6833 (1999).

    CAS  PubMed  Google Scholar 

  88. Bondeson, J., Foxwell, B., Brennan, F. & Feldmann, M. Defining therapeutic targets by using adenovirus: blocking NF-κB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc. Natl Acad. Sci. USA 96, 5668–5673 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Miagkov, A. V. et al. NF-κB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc. Natl Acad. Sci. USA 95, 13859–13864 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Yamamoto, Y. & Gaynor, R. B. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. J. Clin. Invest. 107, 135–142 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Epinat, J. C. & Gilmore, T. D. Diverse agents act at multiple levels to inhibit Rel/NF-κB signal-transduction pathway. Oncogene 18, 6896–6909 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Swinney, D. C. et al. A small molecule ubiquitination inhibitor blocks NF-κB-dependent cytokine expression in cells and rats. J. Biol. Chem. 277, 23573–23581 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Lavon, I. et al. High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-κB activation. Nature Med. 6, 573–577 (2000).Specific inhibition of NF-κB activity in adult mouse liver does not cause liver apoptosis or dysfunction. However, these mice were unable to clear Listeria monocytogenes from the liver and succumbed to sepsis.

    Article  CAS  PubMed  Google Scholar 

  94. Neurath, M. F., Pettersson, S., Meyer zum Buschenfelde, K. H. & Strober, W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-κB abrogates established experimental colitis in mice. Nature Med. 2, 998–1004 (1996).These data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and indicate a potential therapeutic use of p65 antisense oligonucleotides as a new molecular approach for the treatment of patients with Crohn's disease.

    Article  CAS  PubMed  Google Scholar 

  95. Aupperle, K. et al. NF-κB regulation by IκB kinase-2 in rheumatoid arthritis synoviocytes. J. Immunol. 166, 2705–2711 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Campbell, I. K., Gerondakis, S., O'Donnell, K. & Wicks, I. P. Distinct roles for the NF-κB1 (p50) and c-Rel transcription factors in inflammatory arthritis. J. Clin. Invest. 105, 1799–1806 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Q.L. is a Special Research Fellow of the Leukemia and Lymphoma Society. I.M.V. is an American Cancer Society Professor of Molecular Biology. He is supported by grants from the National Institutes of Health, the March of Dimes, the Lebensfeld Foundation, the Wayne and Gladys Valley Foundation and the H.N. and Frances C. Berger Foundation.

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Correspondence to Inder M. Verma.

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IP

MS

rheumatoid arthritis

Glossary

INCONTINENTIA PIGMENTI

(IP). This disease is characterized by abnormalities in ectodermal tissues, including the skin, eyes and central nervous system, and dentition. It is inherited as an X-linked dominant trait and is usually fatal for male fetuses.

ANHIDROTIC ECTODERMAL DYSPLASIA WITH IMMUNODEFICIENCY

(EDA-ID). X-linked and autosomal forms of EDA syndromes are characterized by the poor development of ectoderm-derived structures, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes — ectodysplasin 1 (ED1) and the ectodysplasin A receptor (EDAR) — has shown the protein products to be a new TNF ligand–receptor pair. EDA-ID is regarded as an independent, primary immunodeficiency syndrome owing to unusually severe infections or immunological abnormalities in some EDA patients.

ISOTYPE SWITCHING

When B cells change their class of antibody (immunoglobulin) production from one isotype to another — for example, from IgM to IgG.

ELECTROPHORETIC MOBILITY-SHIFT ASSAY

A technique for detecting DNA–protein complex formation. It involves the incubation of nuclear extracts with a radiolabelled oligonucleotide probe, then separating the probe that has bound nuclear proteins from the free radiolabelled probe by gel electrophoresis, followed by autoradiography.

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Li, Q., Verma, I. NF-κB regulation in the immune system. Nat Rev Immunol 2, 725–734 (2002). https://doi.org/10.1038/nri910

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