Blockade of NF-kappaB activation and donation of nitric oxide: new treatment options in inflammatory bowel disease?
BACKGROUND
Inhibition of NF-kappaB activation has been suggested as an anti-inflammatory treatment strategy in inflammatory bowel disease (IBD). However, NF-kappaB regulated genes like inducible nitric oxide synthase (iNOS) are also involved in cell survival mechanisms.


METHODS
Review of the literature on NF-kappaB activation and iNOS induction in IBD.


RESULTS
In patients with IBD the mucosal immune response is derailed. The nuclear transcription factor NF-kappaB is a key regulator of the inducible expression of many genes involved in immune and inflammatory responses in the gut. Stimuli like oxidative stress, cytokines (IL-1, IL-6, TNF-alpha), bacteria and viruses can release NF-kappaB from their inactive cytoplasmatic form to the nucleus. Drugs like corticosteroids, sulphasalazine, mesalazine and inhibitory cytokines (e.g. IL-10, IL-11) can prevent the activation of NF-kappaB. New, more potent and selective treatment strategies with anti-sense p65, proteasome inhibitors and viral IkappaBalpha expression vectors aim at the prevention of NF-kappaB activation in mucosal macrophages and T lymphocytes. However, NF-kappaB regulated genes are also involved in survival responses of epithelial cells. For example, inhibition of the NF-kappaB mediated induction of iNOS in epithelial cells could block important anti-apoptotic and anti-microbial survival mechanisms. Nitric oxide may also serve in a negative feedback loop to antagonize prolonged activation of NF-kappaB, thereby limiting chronic inflammation.


CONCLUSIONS
Luminal donation of nitric oxide could block NF-kappaB activation. Selective inhibition of NF-kappaB activation in inflammatory cells could be a treatment option in IBD.
Dijkstra
G
G
Dept. of Gastroenterology and Hepatology, University Hospital Groningen, The Netherlands. G.Dijkstra@int.azg.nl
Moshage
H
H
Jansen
P L M
PL
D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II
D016328:NF-kappa B; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II