Blockade of NF-κB 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 antisense 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. Conclusion: 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.