Blockade of NF-kappa B activation and donation of nitric oxide: New treatment options in inflammatory bowel disease?

G Dijkstra*, H Moshage, PLM Jansen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

74 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)37-41
Number of pages5
JournalSCANDINAVIAN JOURNAL OF GASTROENTEROLOGY
Volume37
Publication statusPublished - 2002

Keywords

  • inducible nitric oxide synthase
  • inflammatory bowel disease
  • NF-kappa B
  • nitric oxide
  • NECROSIS-FACTOR-ALPHA
  • COLON EPITHELIAL-CELLS
  • CHRONIC COLITIS
  • SYNTHASE ACTIVITY
  • ULCERATIVE-COLITIS
  • OXIDATIVE STRESS
  • GENE-EXPRESSION
  • DEFICIENT MICE
  • P65 SUBUNIT
  • DNA-BINDING

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