NF-κB regulation in the immune system

Nature Reviews Immunology

Volumn 2, Issue 10, 2002, Pages 725-734

  Li, Qiutang ^a   Verma, Inder M ^a  

^a SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLSALICYLIC ACID; ANTIINFLAMMATORY AGENT; CORTICOSTEROID; I KAPPA B; I KAPPA B KINASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1 ANTIBODY; NONSTEROID ANTIINFLAMMATORY AGENT; T LYMPHOCYTE RECEPTOR; TUMOR NECROSIS FACTOR ANTIBODY; CHUK PROTEIN, HUMAN; CHUK PROTEIN, MOUSE; DNA BINDING PROTEIN; I KAPPA B BETA; IKBKB PROTEIN, HUMAN; IKBKB PROTEIN, MOUSE; IKBKE PROTEIN, HUMAN; IKBKE PROTEIN, MOUSE; NF KAPPAB INHIBITOR ALPHA; NF-KAPPAB INHIBITOR ALPHA; PROTEIN SERINE THREONINE KINASE;

CARCINOGENESIS; CELLULAR IMMUNITY; DISEASE COURSE; DRUG DESIGN; DRUG MECHANISM; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; GENE CONTROL; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; IMMUNOREGULATION; INFLAMMATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; RECEPTOR UPREGULATION; REGULATORY MECHANISM; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; ANIMAL; BIOLOGICAL MODEL; DRUG ANTAGONISM; GENETICS; IMMUNE SYSTEM; IMMUNOLOGY; METABOLISM; MOUSE; MOUSE MUTANT; TRANSACTIVATION;

ANIMALS; DNA-BINDING PROTEINS; HUMANS; I-KAPPA B KINASE; I-KAPPA B PROTEINS; IMMUNE SYSTEM; INFLAMMATION; MICE; MICE, KNOCKOUT; MODELS, IMMUNOLOGICAL; NF-KAPPA B; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION; TRANS-ACTIVATION (GENETICS);

EID: 0036781052     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri910     Document Type: Review

References (96)

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).
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).
3. May, M. J. & Ghosh, S. Rel/NF-κB and IκB proteins: an overview. Semin. Cancer Biol. 8, 63-73 (1997).
4. Silverman, N. & Maniatis, T. NF-κB signaling pathways in mammalian and insect innate immunity. Genes Dev. 15, 2321-2342 (2001).
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).
6. Dechend, R. et al. The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators. Oncogene 18, 3315-3323 (1999).
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.
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).
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).
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).
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).
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).
13. Lee, S. H. & Hannink, M. Characterization of the nuclear import and export functions of IκBε. J. Biol. Chem. 277, 23358-23366 (2002).
14. Tam, W. F. & Sen, R. IκB family members function by different mechanisms. J. Biol. Chem. 276, 7701-7704 (2001).
15. Fenwick, C. et al. A subclass of Ras proteins that regulate the degradation of IκB. Science 287, 869-873 (2000).
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).
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).
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).
19. Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature Immunol. 2, 675-680 (2001).
20. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346-351 (2001).
21. Kelliher, M. A. et al. The death-domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297-303 (1998).
22. Yang, J. et al. The essential role of MEKK3 in TNF-induced NF-κB activation. Nature Immunol. 2, 620-624 (2001).
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).
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).
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).
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).
27. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621-663 (2000).
28. Ben-Neriah, Y. Regulatory functions of ubiquitination in the immune system. Nature Immunol. 3, 20-26 (2002).
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.
30. Rudolph, D. et al. Severe liver degeneration and lack of NF-κB activation in NEMO/IKKγ-deficient mice. Genes Dev. 14, 854-862 (2000).
31. Li, Q., Van Antwerp, D., Mercudo, 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.
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.
33. Li, Q. et al. IKK1-deficient mice exhibit abnormal development of skin and skeleton. Genes Dev. 13, 1322-1328 (1999).
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).
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).
36. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495-1499 (2001).
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.
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, 465-472 (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.
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).
40. Schmidt-Suppnan, M. et al. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell 5, 981-992 (2000).
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).
42. Davin, 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).
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).
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).
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).
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)
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).
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).
49. Kishore, N. et al. IKK-1 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).
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).
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).
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).
53. Yin, L. et al. Defective lymphotoxin-β receptor-induced NF-κB transcriptional activity in NIK-deficient mice. Science 291, 2162-2165 (2001).
54. Tojima, Y. et al. NAK is an IκB kinase-activating kinase. Nature 404, 778-782 (2000).
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)
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).
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).
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).
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).
60. Hoeflich, K. P. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86-90 (2000).
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).
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).
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).
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).
65. Ashburner, B. P., Westerhelde, 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.
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.
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.
68. Funa, B. et al. Enhancement of nuclear factor-κB acetylation by coactivator p300 and HIV-1 Tat proteins. J. Biol. Chem. 277, 4973-4980 (2002).
69. Perkins, N. D. The Rel/NF-κB family: friend and foe. Trends Biochem. Sci. 25, 434-440 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
81. Franzoso, G. et al. Requirement for NF-κB in osteoclast and B-cell development. Genes Dev. 11, 3482-3496 (1997).
82. Kaisho, T. et al. IκB kinase α is essential for mature B-cell development and function. J. Exp. Med. 193, 417-426 (2001).
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, 146-158 (1999).
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).
85. Tak, P. P. & Firestein, G. S. NF-κB: A key role in inflammatory diseases. J. Clin. Invest. 107, 7-11 (2001).
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).
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).
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).
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).
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).
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).
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).
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.
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.
95. Aupperle, K. et al. NF-κB regulation by IκB kinase-2 in rheumatoid arthritis synoviocytes. J. Immunol. 166, 2705-2711 (2001).
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).