For the best experience on the Abcam website please upgrade to a modern browser such as Google Chrome
The NF-κB family of transcription factors plays important roles in the immune system (Ghosh et al., 1998; Li and Verma 2002; Bonizzi and Karin 2004). NF-κB family members regulate the expression of cytokines, inducible nitric oxide synthase (iNOS), cyclo-oxygenase 2 (COX-2), growth factors and inhibitors of apoptosis. They also regulate the expression of effector enzymes in response to ligation of many receptors involved in immunity including T-cell receptors (TCRs), B-cell receptors (BCRs) and members of the Toll-like receptor/IL-1 receptor super family. Additionally, NF-κB plays a role in the development and activity of a number of tissues including the central nervous system (Memet 2006). Moreover, pathological dysregulation of NF-κB is linked to inflammatory and autoimmune diseases as well as cancer.
In mammals, the NF-κB family is composed of five related transcription factors: p50, p52, RelA (p65), c-Rel and RelB (Moynagh 2005; Hoffmann et al., 2006). These transcription factors share homology through a 300 amino acid N-terminal DNA binding/dimerization domain, called the Rel homology domain (RHD). The RHD is a platform where family members can form homodimers and heterodimers, enabling them to bind promoters and enhancer regions of genes to modulate their expression. RelA, c-Rel and RelB contain C-terminal transcriptional activation domains (TADs), which enable them to activate target gene expression. In contrast, p50 and p52 do not contain C-terminal TADs; therefore, p50 and p52 homodimers repress transcription unless they are bound to a protein containing a TAD, such as RelA, c-Rel or RelB or Bcl-3 (a related transcriptional co-activator). Unlike the other NF-κB family members, p50 and p52 are derived from larger precursors, p105 and p100, respectively.
NF-κB proteins are not synthesized de novo; therefore their transcriptional activity is silenced by interactions with inhibitory IκB proteins present in the cytoplasm. There are currently seven identified IκB family members - IκBα, IκBβ, Bcl-3, IκBε, IκBγ and the precursor proteins p100 and p105, which are characterized by the presence of ankyrin repeats.
Two signaling pathways lead to the activation of NF-κB, known as the classical (canonical) pathway and the alternative (non-canonical) pathway (Karin 1999; Tergaonkar 2006; Gilmore 2006; Scheidereit 2006). The common regulatory step in both of these cascades is activation of an IκB kinase (IKK) complex consisting of catalytic kinase subunits (IKKα and/or IKKβ) and the regulatory non-enzymatic scaffold protein NEMO (NF-κB essential modulator also known as IKKγ). Activation of NF-κB dimers is due to IKK-mediated phosphorylation-induced proteasomal degradation of IκB, enabling the active NF-κB transcription factor subunits to translocate to the nucleus and induce target gene expression. NF-κB activation leads to the expression of the IκBα gene, which functions as a negative feedback loop to sequester NF-κB subunits and terminating signaling unless a persistent activation signal is present.
In the canonical signaling pathway, binding of ligand to a cell surface receptor such as a member of the the Toll-like receptor superfamily leads to the recruitment of adaptors (such as TRAF) to the cytoplasmic domain of the receptor (Figure 1). These adaptors in turn recruit the IKK complex which leads to phosphorylation and degradation of the IκB inhibitor. The canonical pathway activates NF-κB dimers comprising RelA, c-Rel, RelB and p50.
Figure 1: The canonical pathway
The binding of ligand to a receptor leads to the recruitment and activation of an IKK complex comprising IKK alpha and/or IKK beta catalytic subunits and two molecules of NEMO. The IKK complex then phosphorylates IκB leading to degradation by the proteasome. NF-κB then translocates to the nucleus to activate target genes.
The non-canonical pathway is responsible for the activation of p100/RelB complexes and occurs during the development of lymphoid organs responsible for the generation of B and T lymphocytes (Figure 2). Only a small number of stimuli are known to activate NF-κB via this pathway and these factors include lymphotoxin B and B cell activating factor (BAFF). This pathway utilizes an IKK complex that comprises two IKKα subunits, but not NEMO. In the non-canonical pathway, ligand induced activation results in the activation of NF-κB inducing kinase (NIK), which phosphorylates and activates the IKKα complex, which in turn phosphorylates p100 leading to the processing and liberation of the p52/RelB active heterodimer. In contrast to p100, p105 undergoes constitutive cleavage to produce p50; whether p105 can undergo inducible processing remains a contentious issue (Hayden and Ghosh 2004; Moynagh 2005).
Figure 2: The non-canonical pathway
Receptor binding leads to the activation of NIK, which phosphorylates and activates an IKK alpha complex that in turn phosphorylates the IκB domain of p100 leading to the liberation of p52/RelB. This heterodimer subsequently translocates to the nucleus to activate target genes.
Asthma is a chronic inflammatory disorder. The pathogenesis of asthma involves the persistent expression of pro-inflammatory cytokines, chemokines and other such inflammatory mediators. The genes of many of these proteins contain NF-κB binding sites within their promoters, suggesting that NF-κB plays a vital role in asthma (Yamamoto and Gaynor 2001; Christman et al., 2000). Indeed, increased NF-κB activity has been observed in the airways of asthmatic patients (Hart et al., 1998).
NF-κB is also implicated in inflammatory bowel disease such as Crohn’s disease and ulcerative colitis (Neurath et al., 1998; Schreiber et al., 1998). NF-κB activation is evident in biopsies from such patients and treatment of patients with steroids decreases NF-κB activity in biopsies as well as reducing the clinical symptoms of disease.
Furthermore, NF-κB is involved in the pathophysiology of the autoimmune disorder rheumatoid arthritis (RA). NF-κB itself is upregulated in RA and cytokines such as TNFα that activate NF-κB are elevated in the synovial fluid of patients with RA (Feldmann et al., 1996; Roman-Blas and Jimenez, 2006).
In addition to the roles that NF-κB plays in inflammatory diseases, constitutive activation of the NF-κB pathway is involved in some forms of cancer such as leukemia, lymphoma, colon cancer and ovarian cancer (Rayet and Gelinas, 1999). Mutations that can lead to such tumors include those that inactivate IκB proteins as well as amplifications and rearrangements of genes encoding the NF-κB transcription factor subunits. However, more commonly it is thought that changes in the upstream pathways that lead to NF-κB activation become deregulated in cancer.
Bonizzi G & Karin M (2004). The two NFkB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 25: 280–288.
Christman JW, Sadikot RT, Blackwell TS (2000). The role of nuclear factor-kappa B in pulmonary diseases. Chest. 117:1482–1487
Feldmann, Brennan FM, Maini RN (1996). Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440.
Ghosh S, May MJ, Kopp EB (1998). NFkB and Rel proteins: evolutionary conserved mediators of immune responses. Annu. Rev. Immunol. 16: 225–260.
Gilmore TD (2006). Introduction to NFkB: players, pathways, perspectives. Oncogene. 25: 6680–6684.
Hart LA, Krishnan VL, Adcock IM, Barnes PJ, Chung KF (1998). Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med.158:1585–1592
Hayden MS, Ghosh G (2004). Signaling to NFkB. Genes Dev. 18: 2195–2224.
Hoffmann A, Natoli G, Ghosh G (2006). Transcriptional regulation via the NFkB signaling module. Oncogene. 25: 6706–6716.
Karin M (1999). How NFkB is activated: the role of the IkB kinase (IKK) complex. Oncogene. 18: 6867–6874.
Li Q & Verma IM (2002). NFkB regulation in the immune system. Nat Rev Immunol. 2: 725–734.
Memet S (2006). NFkB functions in the nervous system: From development to disease. Biochem Pharmacol. 72: 1180–1195.
Moynagh PN (2005). The NFkB pathway. J Cell Sci. 118: 4389–4392.
Neurath MF, Fuss I, Schurmann G, Pettersson S, Arnold K, Muller-Lobeck H, Strober W, Herfarth C, Buschenfelllde KH (1998). Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann N Y Acad Sci. 859: 149–159.
Rayet B & Gelinas C (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 18: 6938–6947.
Roman-Blas JA & Jimenez SA (2006). NFkappaB as a potential therapeutic target in osteoarthritis and rheumatoid arthritis. Osteoarthritis Cartilage. 14: 839–848.
Scheidereit C (2006). IkB kinase complexes: gateways to NFkB activation and transcription. Oncogene. 25: 6685–6705.
Schreiber S, Nikolaus S, Hampe J (1998). Activation of nuclear factor kappa B inflammatory bowel disease. Gut. 42: 477–484
Tergaonkar V (2006). NFkB pathway: A good signaling paradigm and therapeutic target. Int J Biochem Cell Biol. 38: 1647–1653.
Yamamoto Y & Gaynor RB (2001). Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest.107:135–142