Given the important role that NF-kB plays in the regulation of a large number of proinflammatory genes, there is a growing interest in targeting it in order to affect the inherent redundancy of the inflammatory cascade. A large body of evidence links the NF-kB pathway to the dysregulated inflammation that is characteristic of diseases such as sepsis and acute respiratory distress syndrome. Several of the genes that comprise the complex network contributing to this dysregulated inflammation and are regulated at the transcriptional level by NF-kB, including the cytokines IL-1? and TNF-alpha, chemokines such as IL-6, IL-8 and macrophage chemotactic protein-1; cell adhesion molecules such as vascular cell adhesion molecule 1 and intercellular adhesion molecule 1; growth factors such as granulocyte macrophage colony-stimulating factor and granulocyte colony stimulating factor; as well as additional proinflammatory genes such as inducible nitric oxide synthase.
Agents Known to Inhibit NF-kB: Pharmacoglogical agents inhibit NF-kB at one of its activation steps, and several classes of drugs are well-known NF-kB inhibitors. such agents include the following: See also
glucocorticoids such as dexamethasone and prednisone
immunosuppressants such as cyclosporine, tacrolimus, and deoxyspergualin
nonsteroidal anti-inflammatory drugs such as aspirin, sodium slicylate and tepoxalin.
capsaicin
Helenalin: is an inhibitor of NF-kB
hypericin
epigallocatechin-e-gallate (EGCG) which is the major polyphenol present in green tea is a potential novel, safe, and nontoxic strategy for inhibiting NF-kB.
SN50
Bacterial toxins or virulence factors:
Microbes interfere with the activation of NF-kB at various parts of the signaling pathway. First part these pathways can inhibit is the pathway proximal to the phosphorylation and degradation of IkB. An example of this is provided by vaccinia virus, which produces a viral homologue of MyK88 which antagonizes MyD88 dependent activaiton of NF-kB.
The ability to intefere with the degradation of IkB is another strategy employed by some pathogens. For example, the measles virus is able to prevent phosphorylation of IkBalpha in nueronal cells.
Some pathogens are able to interfere with NFkB activation downstream from the degradation of IkB. For example, the African swin fever virus makes a viral protein which is a homologue of IkB which can bind to NFkB following degradation of host IkB and so inhibits nuclear localization of dimers.
Some pathgoenic bacteria also interfere with the ability of NFkB dimers to translocate into the nucleus as by perhaps by directly interfering with the ability of NF-kB to bind DNA.
Yersinia and Salmonella inhibit NF-kB activation.
antrax bacterium induces apoptosis of TLR4 activated macrophages through its lethal toxin, whose lethal factor catalytic subunit prevetns p38 activaiton by cleavage of the upstream kinase MKK6 (Park et al., 2002)
Negative Regulation of NF-kB: The IkB-alpha gene (a subtype of the class of IkB inhibitors and clearly taregeted in the case of inflammatory stimulation) also contains an NF-kB-responsive element in its promoter which leads to upregulation by NF-kB and to resynthesis of the inhibitor molecule which can now catch and binding newly synthesised as well as previously released NF-kB. This acts as an autoregulatory loop (negative feedback) mechanism, keeping the NF-kB levels in balance and gene transcription under tight control.