Article Text

Download PDFPDF

Activation of nuclear factor κB as a target for anti- inflammatory therapy
  1. Christian Albrechts University, First Department of Medicine, Schittenhelmstrasse 12, 24105 Kiel, Germany e-mail:s.schreiber{at}

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


Transcription factors are small proteins which specifically regulate the expression of genes. A pivotal step in transcriptional regulation is the physical binding of these regulatory proteins to DNA sites in gene promoter regions. Binding specificity is determined by the nucleotide sequence of the binding site. Nuclear factor κB (NF-κB) was defined by its ability to bind to a 10 base pair oligonucleotide motif first identified in the enhancer region of the immunoglobulin κ light chain gene. NF-κB, which has recently been shown to regulate most inflammation genes, was originally described as a heterodimeric complex of two subunits, p65 and p50.1 ,2

Proteins of the NF-κB family are found constitutively in the cytoplasm of most mammalian cells. In resting cells, they are sequestered in the cytoplasm by inactivating molecules which are mainly members of the inhibitor κB family (IκB).1 ,2Activation of NF-κB requires release of the molecule from its inhibitor IκB, which is initiated by serine phospyhorylation through two kinases, the inhibitor κB kinases (IKK) α and β. Activation of the IKK can be initiated by several pathways including the cellular kinases NIK and MEKK1 and the sphingomyelin pathway.3-5Tumour necrosis factor (TNF) seems to be one of the main cellular activators of the IκB kinases and hence of IκB degradation and NF-κB activation.

There is little doubt that increased production of TNF and other inflammatory mediators plays a pivotal immunoregulatory role in several chronic inflammatory gastrointestinal diseases, including Crohn’s disease6 ,7 and ulcerative colitis.8 ,9 High levels of NF-κB activation have been shown both in Crohn’s disease10 ,11 and animal models of inflammatory bowel disease.12 Therefore, it has been suggested that chronic activation of NF-κB in inflammatory bowel disease may be the primary event in many of the regulatory phenomena described in the pathophysiology of this disease.

Effective anti-inflammatory therapies for inflammatory bowel disease have been defined largely empirically. Steroids13 ,14 as well as anti-TNF-agents15 ,15a are highly effective in the treatment of acute or chronic active disease. Steroids16 ,17 and interleukin-1018 seem to exert their main anti-inflammatory potency by inhibition of NF-κB activation. Aminosalicylates have a moderate anti-inflammatory potency in acute disease and are used to maintain remission in ulcerative colitis.19 Aminosalicylates20-26 and sulphasalazine27 also inhibit activation of NF-κB, although the mechanism was not uncovered until recently.

Yin and coworkers have looked for cellular targets that regulate NF-κB activation and which may be influenced by salicylates. At therapeutically relevant concentrations (1–5 mmol) salicylates strongly inhibited NIK and TNF-α activated expression of inflammation genes. Aspirin and sodium salicylate but not dexamethasone or indomethacin strongly inhibited IKK-β (but not IKK-α) activity both in vitro and in vivo. Salicylates seemed to compete with ATP by binding non-covalently and reversibly to IKK-β.

These findings have great implications for our understanding of the actions of anti-inflammatory drugs. Glucocorticoids and novel agents such as interleukin-10 reduce activation of NF-κB but apparently via mechanisms other than those used by salicylates. This might explain why steroids, in contrast to aminosalicylates, are not capable of maintaining remission although they have a much greater anti-inflammatory potency. In addition, the identification of IKK-β as a specific target for aspirin as well as sodium salicylates may facilitate the development of a “super-aspirin” with optimised anti-inflammatory properties.


NF-κB comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response. NF-κB is sequestered in the cytoplasm by inhibitory proteins, IκB, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-α and IKK-β, which phosphorylate IκB, leading to its degradation and translocation of NF-κB to the nucleus. IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-α or by overexpression of the cellular kinases MEKK1 and NIK. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-β activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-β to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-β, thereby preventing activation by NF-κB of genes involved in the pathogenesis of the inflammatory response.