The choice between life and death is one of the major events in regulation of the immune system. T cells that specifically recognize viral or bacterial antigens are selected to survive and proliferate in response to infection, whereas those that are self-reactive are eliminated via apoptosis. Even the survival of alloreactive T cells requires their proper costimulation and, when infection subsides, the activated T cells are eliminated. A major regulator of such life or death decisions is the transcription factor NF-κB. However, NF-κB cannot function alone. A variety of mechanisms exist to modulate its activity and thereby affect the ultimate outcome of a cell's fate.
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Baeuerle, P. A. & Henkel, T. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141–179 (1994).
Barnes, P. J. & Karin, M. NF-κB – A pivotal transcription factor in chronic inflammatory diseases. New Engl. J. Med. 336, 1066–1071 (1997).
Sha, W. C., Liou, H. C., Tuomanen, E. I. & Baltimore, D. Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses. Cell 80, 321–330 (1995).
Alcamo, E. et al. Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment. J. Immunol. 167, 1592–1600 (2001).
Franzoso, G. et al. Mice deficient in NF-κB/p52 present with defects in humoral responses, germinal center reactions, and splenic reactions. J. Exp. Med. 187, 147–159 (1998).
Attar, R. M. et al. Genetic approaches to study Rel/NF-κB/IκB function in mice. Semin. Cancer Biol. 8, 93–101 (1997).
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).
Beg, A. A. & Baltimore, D. An essential role for NF-κB in preventing TNF-α induced cell death. Science 274, 782–784 (1996).
Wang, C.-Y., Mayo, M. W. & Baldwin, A. S. Jr TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274, 784–787 (1996).
Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. Suppression of TNFα-induced apoptosis by NF-κB. Science 274, 787–789 (1996).
Liu, Z.-G., Hu, H., Goeddel, D. V. & Karin, M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis, while NF-κB activation prevents cell death. Cell 87, 565–576 (1996).
Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).
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).
Solan, N. J., Miyoshi, H., Bren, G. D. & Paya, C. V. RelB cellular regulation and transcriptional activity are regulated by p100. J. Biol. Chem. 277, 1405–1418 (2002).
Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).
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).
Delhase, M., Hayakawa, M., Chen, Y. & Karin, M. Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation. Science 284, 309–313 (1999).
Li, Z.-W. et al. The IKKβ subunit of IκB kinase (IKK) is essential for NF-κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).
Zhong, H., SuYang, H., Erdjument-Bromage, H., Tempst, P. & Ghosh, S. The transcriptional activity of NF-κB is regulated by the IκB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 89, 413–424 (1997).
Sizemore, N., Leung, S. & Stark, G. R. Activation of phosphatidylinositol 3-kinase in response to Interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit. Mol. Cell. Biol. 19, 4798–4805 (1999).
Madrid, L. V. et al. Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-κB. Mol. Cell. Biol. 20, 1626–1638 (2000).
Beg, A. A., Sha, W. C., Bronson, R. T., Ghosh, S. & Baltimore, D. Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376, 167–169 (1995).
Baud, V. & Karin, M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell. Biol. 11, 372–377 (2001).
Makris, C. et al. Female mice heterozygote for IKKγ/NEMO deficiencies develop a genodermatosis similar to the human X-linked disorder Incontinentia Pigmenti. Mol. Cell 15, 969–979 (2000).
Doi, T. S. et al. Absence of TNF rescues RelA-deficient mice from embryonic lethality. Proc. Natl Acad. Sci. USA 96, 2994–2999 (1999).
Rosenfeld, M. E., Prichard, L., Shiojiri, N. & Fausto, N. Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR1 double knockout mice. Am. J. Pathol. 156, 997–1007 (2000).
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).
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).
Baldwin, A. S. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB. J. Clin. Invest. 107, 241–246 (2001).
Deveraux, Q. L. et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223 (1998).
Chu, Z. L. et al. Suppression of TNF-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-κB control. Proc. Natl Acad. Sci. USA 94, 10057–10062 (1997).
Hong, S. Y. et al. Involvement of two NF-κB binding elements in TNFα-, CD40-, and Epstein-Barr virus latent membrane protein 1-mediated induction of the cellular inhibitor of apoptosis protein 2 gene. J. Biol. Chem. 275, 18022–18028 (2000).
Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V. & Baldwin, A. S. Jr NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680–1683 (1998).
Shu, H. B., Takeuchi, M. & Goeddel, D. V. The TNF2 signal transducers TRAF2 and c-IAP1 are components of the TNF1 signaling complex. Proc. Natl Acad. Sci. USA 93, 13973–13978 (1996).
Liston, P. et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379, 349–353 (1996).
Takahashi, R. et al. A single BIR domain of XIAP sufficient for inhibiting caspases. J. Biol. Chem. 273, 7787–7790 (1998).
Deveraux, Q. L. et al. Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases. EMBO J. 18, 5242–5251 (1999).
Chai, J. et al. Structural basis of caspase-7 inhibition by XIAP. Cell 104, 769–780 (2001).
Huang, Y. et al. Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the IBR domain. Cell 104, 781–790 (2001).
Riedl, S. J. et al. Structural basis for the inhibition of caspase-3 by XIAP. Cell 104, 791–800 (2001).
Conte, D., Liston, P., Wong, J. W., Wight, K. E. & Korneluk, R. G. Thymocyte-targeted overexpression of xiap transgene disrupts T lymphoid apoptosis and maturation. Proc. Natl Acad. Sci. USA 98, 5049–5054 (2001).
Harlin, H., Reffey, S. B., Duckett, C. S., Lindsten, T. & Thompson, C. B. Characterization of XIAP-deficient mice. Mol. Cell. Biol. 21, 3604–3608 (2001).
Stehlik, C. et al. NF-κB-regulated xiap gene expression protects endothelial cells from TNFα-induced apoptosis. J. Exp. Med. 188, 211–216 (1998).
Tang, G. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001).
Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517–521 (1997).
Irmler, M. et al. Inhibition of death receptor signals by cellular FLIP. Nature 388, 190–195 (1997).
Yeh, W. C. et al. Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embyronic development. Immunity 12, 633–642 (2000).
Shu, H. B., Halpin, D. R. & Goeddel, D. V. Casper is a FADD- and caspase-related inducer of apoptosis. Immunity 6, 751–763 (1997).
Kreuz, S., Siegmund, D., Scheurich, P. & Wajant, H. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol. Cell. Biol. 21, 3964–3973 (2001).
Lin, E. Y., Orlofsky, A., Berger, M. S. & Prystowsky, M. B. Characterizaiton of A1, a novel hemopoietic-specific early-response gene with sequence similarity to bcl-2. J. Immunol. 151, 1979–1988 (1993).
Wang, C. Y., Guttridge, D. C., Mayo, M. W. & Baldwin, A. S. Jr NF-κB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol. Cell. Biol. 19, 5923–5929 (1999).
Grumont, R. J., Rourke, I. J. & Gerondakis, S. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev. 13, 400–411 (1998).
Lee, H. H., Dadgostart, H., Cheng, Q., Shu, J. & Cheng, G. NF-κB-mediated upregulation of Bcl-X and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proc. Natl Acad. Sci. USA 96, 9136–9141 (1999).
Zong, W. X., Edelstein, L. C., Chen, C., Bash, J. & Gelinas, C. The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis. Genes Dev. 13, ′–′ (1999).
Hamasaki, A. et al. Accelerated neutrophil apoptosis in mice lacking A1-a, a subtype of the bcl-2-related A1 gene. J. Exp. Med. 188, 1985–1992 (1998).
Tamatani, M. et al. TNF induces Bcl-2 and Bcl-x expression through NF-κB activation in primary hippocampal neurons. J. Biol. Chem. 274, 8531–8538 (1999).
Tsukahara, T. et al. Induction of Bcl-x(L) expression by human T-cell leukemia virus type 1 Tax through NF-κB in apoptosis-resistant T-cell transfectants with Tax. J. Virol. 73, 7981–7987 (1999).
Khoshnan, A. et al. The NF-κB cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. J. Immunol. 165, 1743–1754 (2000).
Chen, C., Edelstein, L. C. & Gelinas, C. The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bel-x(L). Mol. Cell. Biol. 20, 2687–2695 (2000).
Grossmann, M. et al. The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J. 19, 6351–6360 (2000).
Bentires-Alj, M. et al. Inhibition of the NF-κB transcription factor increases Bax expression in cancer cell lines. Oncogene 20, 2805–2813 (2001).
Wu, M. X., Ao, Z., Prasad, K. V., Wu, R. & Schlossman, S. F. IEX-1L, an apoptosis inhibitor involved in NF-κB-mediated cell survival. Science 281, 998–1001 (1998).
Schafer, H., Arlt, A., Trauzold, A., Hunermann-Jansen, A. & Schmidt, W. E. The putative apoptosis inhibitor IEX-1L is a mutant nonspliced variant of p22(PRG1/IEX-1) and is not expressed in vivo. Biochem. Biophys. Res. Commun. 262, 139–145 (1999).
Lee, S. Y. et al. TRAF2 is essential for JNK but not NF-κB activation and regulates lymphocyte proliferation and survival. Immunity 7, 703–713 (1997).
Verheij, M. et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380, 75–79 (1996).
Natoli, G. et al. Activation of SAPK/JNK by TNFR1 through a noncytotoxic TRAF2-dependent pathway. Science 275, 200–203 (1997).
Tournier, C. et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288, 870–874 (2000).
De Smaele, E. et al. Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313 (2001).
Javelaud, D. & Besancon, F. NF-κB activation results in rapid inactivation of JNK in TNFα-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-κB. Oncogene 20, 4365–4372 (2001).
Fornace, A. J. J., Jackman, J., Hollander, M. C., Hoffman-Liebermann, B. & Liebermann, D. A. Genotoxic-stress-response genes and growth-arrest genes. gadd, MyD, and other genes induced by treatments eliciting growth arrest. Ann. NY Acad. Sci. 663, 139–153 (1992).
Lenczowski, J. M. et al. Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis. Mol. Cell. Biol. 17, 170–181 (1997).
Lin, D. et al. A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature Cell Biol. 2, 540–547 (2000).
Duckett, C. S. & Thompson, C. B. CD30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev. 11, 2810–2821 (1997).
Arch, R. H., Gedrich, R. W. & Thompson, C. B. Translocation of TRAF proteins regulates apoptotic threshold of cells. Biochem. Biophys. Res. Commun. 272, 936–45 (2000).
Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).
Leo, E. et al. TRAF1 is a substrate of caspases activated during TNFRα-induced apoptosis. J. Biol. Chem. 276, 8087–8093 (2001).
Schwenzer, R. et al. The human TNF TRAF1 is upregulated by cytokines of the TNF ligand family and modulates TNF-induced activation of NF-κB and c-Jun N-terminal kinase. J. Biol. Chem. 274, 19368–19374 (1999).
Tang, G., Yang, J., Minemoto, Y. & Lin, A. Blocking caspase-3-mediated proteolysis of IKKβ suppresses TNFα-induced apoptosis. Mol. Cell 8, 1005–1016 (2001).
Reuther, J. Y. & Baldwin, A. S. Jr Apoptosis promotes a caspase-induced amino-terminal truncation of IκBα that functions as a stable inhibitor of NF-κB. J. Biol. Chem. 274, 20664–20670 (1999).
Barkett, M., Xue, D., Horvitz, H. R. & Gilmore, T. D. Phosphorylation of IκBα inhibits its cleavage by caspase CPP32 in vitro. J. Biol. Chem. 272, 29419–29422 (1997).
Levkau, B., Scatena, M., Giachelli, C. M., Ross, R. & Raines, E. W. Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-κB loop. Nature Cell Biol. 1, 227–233 (1999).
Clem, R. J. et al. c-IAP1 is cleaved by caspases to produce a proapoptotic C-terminal fragment. J. Biol. Chem. 276, 7602–7608 (2001).
Clem, R. J. et al. Modulation of cell death by Bcl-XL through caspase interaction. Proc. Natl Acad. Sci. USA 95, 554–559 (1998).
Fujita, N., Nagahashi, A., Nagashima, K., Rokudai, S. & Tsuruo, T. Acceleration of apoptotic cell death after the cleavage of Bel-XL protein by caspase-3-like proteases. Oncogene 17, 1295–1304 (1998).
Nakagawa, T. & Yuan, J. Cross-talk between two cysteine protease families: activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 150, 887–894 (2000).
Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFβ, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).
Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).
Freire-de-Lima, C. G. et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403, 199–203 (2000).
Orth, K. et al. Disruption of signaling by Yersinia effector YopJ, a ubiquitin-like protein protease. Science 290, 1594–1597 (2000).
Mills, S. D. et al. Yersinia enterocolitica induces apoptosis in macrophages by a process requiring functional type III secretion and translocation mechanisms and involving YopP, presumably acting as an effector protein. Proc. Natl Acad. Sci. USA 94, 12638–12643 (1997).
Kasof, G. M. et al. TNFα induces the expression of DR6, a member of the TNF receptor family, through activation of NF-κB. Oncogene 20, 7965–7975 (2001).
Ravi, R. et al. Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-κB. Nature Cell Biol. 3, 409–416 (2001).
Zheng, Y. et al. NF-κB RelA (p65) is essential for TNFα-induced fas expression but dispensable for both TCR-induced expression and activation-induced cell death. J. Immunol. 166, 4949–4957 (2001).
Asea, A. et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nature Med. 6, 435–442 (2000).
Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).
Medzhitov, R. CpG DNA: security code for host defense. Nature Immunol. 2, 15–16 (2001).
Mitchell, T. C. et al. Immunological adjuvants promote activated T cell survival via induction of Bcl-3. Nature Immunol. 2, 397–402 (2001).
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).
We thank C. Adams for help with manuscript preparation and A. Fornace for disclosing unpublished results. Supported by grants from the National Institutes of Health, the State of California Cancer Research Program and the American Cancer Society.
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Karin, M., Lin, A. NF-κB at the crossroads of life and death. Nat Immunol 3, 221–227 (2002). https://doi.org/10.1038/ni0302-221
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