NF-kappaB signaling: pros and cons of altering NF-kappaB as a therapeutic approach.
The transcription factor, nuclear factor-kappaB (NF-kappaB), is a dominant regulator of the expression of hundreds of genes, many of which play important roles in the regulation of inflammation and programmed cell death (apoptosis). Since the discovery of NF-kappaB in the mid 1980s, this transcription factor has been the subject of intense investigation. Excess or inappropriate activation of NF-kappaB has been observed in human inflammatory bowel disease and in a host of other inflammatory diseases and type of cancer. Functional studies in animals have shed light on the role of NF-kappaB in broader pathophysiological contexts. From such studies, it has become quite clear that NF-kappaB plays unique and distinct functions in different cell types. Because of the importance of NF-kappaB in signaling inflammation, and in inhibiting programmed cell death, many pharmaceutical companies are developing small-molecule inhibitors of this pathway. In this article, we evaluate the relative pros and cons of blocking NF-kappaB as a therapeutic approach for inflammatory bowel disease. On the basis of the results of studies in animals that have primarily used genetic approaches to inhibit NF-kappaB activity, we suggest that there are certain niche indications for blocking NF-kappaB in inflammatory bowel disease that offer particular promise.
Egan
Laurence J
LJ
Clinical Science Institute, University College Hospital, Galway, Ireland. laurence.egan@nuigalway.ie
Toruner
Murat
M
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000503:physiopathology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction
D016328:NF-kappa B