The transcription factor NF-κB induces expression of a variety of genes involved in mediating the immune response, including cytokines, chemokines, and adhesion molecules (reviewed in Gut 1998;43:856-60
). The NFκB family is comprised of several genes whose products associate to form dimers, most commonly consisting of p65 and p50 in human cells. The dimer complex is maintained in an inactive state in the cellular cytoplasm by association with the inhibitory protein IκB. Upon phosphorylation by kinases, known as κ kinases, IκB undergoes ubiquitination and degradation, thereby allowing NF-κB to translocate into the nucleus and activate transcription.
Due to the significance of NF-κB in immune regulation, perhaps it is not surprising that several anti-inflammatory agents can exert their effect by altering NF-κB signaling (Fig 1). For example, corticosteroids inhibit NF-κB activity by inducing production of the inhibitory binding protein IκB. Wahl et al. (J Clin Invest 1998;101:1163-174
) discovered that sulfasalazine interfers with NF-κB activation by preventing IκB degradation. These findings are of particular interest because several studies implicate NF-κB activation in mediating chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis, and gastroenteric infections including Helicobacter pylori.
It is generally considered that the therapeutic effect of aspirin resides in its ability to inhibit prostaglandin synthesis. However, previous studies demonstrated that aspirin also blocks activation of NF-κB. In the November 5th issue of Nature (1998;396:77-80
), Yin et al. identify the mechanism by which aspirin and sodium salicylates inhibit NF-κB. In the presence of stimulation by the potent cytokine tumor necrosis factor-alpha (TNF-α), aspirin specifically inhibits the kinase responsible for phosphorylating IκB, IκB kinase-β. Therefore, NF-κB is maintained in its inactive form complexed with IκB in the cytoplasm and transcription of genes involved in the inflammatory response is abrogated. Thus, an additional anti-inflammatory mechanism for aspirin has been delineated.
As with many immunomodulatory therapies, the therapeutic efficacy of the agents is hampered by unwanted toxicity, in part due to nonspecific activities. Aspirin is no exception. Therefore, the delineation of the precise pathways by which drugs exert their effects should allow for the development of improved therapeutic agents that can be directed towards altering specific pathways. The pleitrophic signals that NF-κB regulates indicate a level of complexity that we are only beginning to understand. Therefore, the potential development of novel therapeutic interventions with reduced toxicity for the management of chronic inflammatory conditions is awaited with anticipation.
Nicola L. Jones, MD, FRCPC
Philip M. Sherman, MD, FRCPC
The Hospital for Sick Children, University of Toronto, Toronto, Canada