NF-kB Activation Inhibitors

Definition
NF-?B, a eukaryotic transcription factor plays an important role in inflammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes. It consists of homo- or heterodimers of different subunits, which belong to a family of Rel/NF-?B proteins. In unstimulated cells, NF-?B is sequestered in the cytoplasm in an inactive form, bound to regulatory proteins called inhibitors of ?B (I?B), of which I?Ba and I?Bß are considered to be the most important. I?Ba is associated with transient NF-?B activation, whereas I?Bß is involved in sustained activation1.

Related Peptides
Like NF-?B, I?Bs are also members of a multigene family containing seven known mammalian members including I?Ba, I?Bß, I?B??, I?Be, bcl-3, the precursor Rel-proteins p100 and p105, and one Drosophila I?B named cactus1.

Discovery
Baeuerle, P.A. et al., discovered IkB, an NF-kB inhibitor, in 1988 1.

Structural Characteristics
The IkB family is characterized by the presence of multiple copies of ankyrin repeats, which are protein-protein interaction motifs that interact with NF-kB via the RHD. Upon appropriate stimulation, IkB is phosphorylated mainly by the IkB kinases (IKKs, especially IKK-a and IKK-b), polyubiquitinated by a ubiquitin ligase complex, and degraded by the 26S proteasome. Close to the C-terminal end of the RHD lies the Nuclear Localization Signal (NLS) which is essential for the transport of active NF-kB complex into the nucleus 1.

Mode of Action
NF-?B activation is stimulated by a pro-oxidative cell status, especially by an increased presence of H2O2 . It is believed that ROS regulate the activity of NF-?B by modifying some of the links in its complex activating cascade: (a) Oxidation of the key sites in the kinases that phophorylate and activate I?B kinases, which in turn phosphorylate the I?B inhibitory proteins, (b) Redox modulation of I?B kinase activity, also, and (c) modulation of the transport of the activated NF-?B from the cytoplasm into the nucleus 1.

NF-?B dimers are held in the inactive state by a family of inhibitors called I-kB. Receptor signaling leads to activation of a multisubunit I-Bk kinase (IKK) complex which phosphorylates I-kB on two key serines. Phosphorylation of I-kB marks it for degradation by the ubiquitin pathway, so that the NF-?B dimer is liberated to translocate to the nucleus, bind DNA and activate transcription. In most resting cells, NF-?B is sequestered in the cytoplasm in an inactive form associated with inhibitory molecules, such as I?Ba, I?Bß, I?B?, p105, and p100. This interaction blocks the ability of NF-?B to bind to DNA and results in the NF-?B complex being primarily localized to the cytoplasm due to a strong nuclear export signal in I?Ba 3.

Certain antioxidants have been shown to inhibit NF-?B activation by acting as general free-radical scavengers. Out of these antioxidants, some of the most extensively studied in the context of NF-?B include glutathione, N-acetyl-cysteine (NAC), a- lipoic acid, and pyrrolidinedithiocarbamate (PDTC) 1.

In 1998 it was confirmed that aspirin and sodium salicylate are competitive inhibitors of the ATP-binding site of IKK-ß, thereby impairing the phosphorylation of I?Bs and subsequent activation of NF-?B. Another popular nonsteroidal anti-inflammatory drug, Sulfasalazine was found to prevent NF-?B activation by blocking I?B phosphorylation and degradation. Sulfasalazine is cleaved to 5-amino-salicylic acid (5-ASA) and sulfapyridine following oral administration; in a recent study it was reported that 5-ASA is the metabolite which inhibits both IKK-a, and IKK-ß kinase activity in mouse colon cells 1.

Functions
Cytokine killer cell activity against tumor cells is amplified by NF-?B inhibitors. The fact that some antioxidants have already been demonstrated to be strong inhibitors of NF-?B activation may be one of the pathways by which they protect against cancers naturally, and also opens a promising avenue in the association between Tumor Necrosis Factor (TNF) and antioxidants in cancer therapy1.

References
1.Pande V, Ramos MJ (2005). NF- kappaB in Human Disease: Current Inhibitors and Prospects for De Novo Structure Based Design of Inhibitors. Curr Med Chem., 12(3):357-374.
2.Baeuerle PA, Baltimore D (1988). I?B: a specific inhibitor of the NF-kB transcription factor. Science, 242:540–546.
3.Hoffmann A, Levchenko A, Scott ML, Baltimore D (2002). The IkB-NF-kB signaling module: temporal control and selective gene activation. Science, 298:1241-1245

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