Article Text


The complicated path to true causes of disease: role of nuclear factor κB in inflammatory bowel disease
  1. S Schreiber
  1. Correspondence to:
    Professor S Schreiber
    Hospital for General Internal Medicine and Institute for Clinical Molecular Biology, Christian-Albrechts-University, Schittenhelmstrasse 12, 24105 Kiel, Germany;

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Challenging our understanding of the role of nuclear factor κB activation in the pathophysiology of intestinal inflammation in human inflammatory bowel disease

Nuclear factor kappa B (NFκB) was discovered as a transcription factor some 15 years ago.1 Since then the protein has been linked to early pathophysiological events in a host of inflammatory conditions. NFκB, in most instances, is a heterodimer composed of a p50 and p65 subunit. In most mammalian cells NFκB is found in the resting state in the cytoplasm where it is bound in a complex to a protein that is a member of a family of specific inhibitors (IKK). Following phosphorylation, the inhibitor is rapidly degraded and the released NFκB migrates within minutes into the nucleus where it can specifically induce gene expression by binding to sequence defined DNA elements in gene promoter regions.

Even after more than a decade of mechanistic and clinical studies, the role of NFκB in intestinal inflammation is not fully understood as its activity as a transcription factor is rather promiscuous. While activation of NFκB is a strong inducer of expression of proinflammatory molecules, the sequences of many genes encoding for proteins involved in contrainflammatory regulation also have NFκB binding sites. In addition, dimers with a different composition (that is, p50-p50 homodimers) appear to exist as endogenous inhibitors of NFκB (p65) induced gene activation.2

In Crohn’s disease, mechanistic data have been generated in an animal model that undoubtedly demonstrated that activation of NFκB is intimately linked to mucosal inflammation and destruction.3 The use of antisense constructs to silence NFκB (p65) greatly improved inflammatory lesions in the murine interleukin 10 knockout model of inflammatory bowel disease (IBD) and also resolved inflammatory events in human intestinal cells from patients with IBD.3 Therefore, NFκB (p65) was thought to be one of the main drivers of the inflammatory reaction. This mechanistic proof was supported by descriptive studies reporting high levels of NFκB (p65) activation in the intestinal mucosa of patients with IBD.4,5 Activation of NFκB therefore appeared to be a hallmark of the pathophysiology of IBD. Clinical development of the use of antisense constructs to silence NFκB (p65) has therefore begun.

The first question on the true role of NFκB in the pathophysiology of IBD arose when the genetic aetiology of Crohn’s disease was unveiled. The discovery of NOD2 (CARD15) as a disease gene demonstrated a series of genetic defects that led to a deficit in NFκB activation in various cell types in response to bacterial stimulation.6–8 This apparent contradiction was resolved through a pathophysiological model in which mucosal barrier function (that is, maintained by “controlled” NFκB activation) was impaired by genetic variants in the NOD2 gene.9 The defect in NOD2 mediated NFκB activation in response to bacterial stimulation then leads to compromised host defence which allows the mucosal barrier to be over run with non-pathological “normal” bowel flora. This model allows for uncontrolled widespread activation of NFκB as the final consequence of a defective innate immune barrier. As a possible non-genetic mechanism to trigger disease manifestation, simplification of the flora was suggested that would lead to a higher invasive pressure of the remaining reduced number of normal bacterial species.10

We are now confronted with yet another finding that is difficult to integrate into the current model of pathophysiology. In this issue of Gut, Andresen and colleagues11 describe high levels of NFκB activation in collagenous colitis that are indistinguishable by means of immunohistology and cell biology from the pattern of NFκB activation found in ulcerative colitis (see page 503). The finding is supported by similar patterns of IKK deactivation and increased activation of NFκB target genes, respectively. However, collagenous colitis and ulcerative colitis are distinctly different diseases with regard to their microscopic and macroscopic pathology. Hence the findings of Andresen and colleagues11 would imply that NFκB activation is not as important as previously believed in the pathophysiology of the destructive mucosal inflammatory reaction in IBD and could therefore be an epiphenomenon. If future work supports this notion, our understanding of the role of NFκB activation in the pathophysiology of intestinal inflammation may be challenged. At present it is difficult to seamlessly integrate these new findings into a unifying hypothetical model. Further work on the spatial and cellular distribution of NFκB activation in the mucosa of IBD patients and in other inflammatory conditions is necessary. Clinical results of ongoing therapeutic studies in which NFκB (p65) is specifically silenced by rectal topical application of an antisense construct may be a pivotal step forward in our understanding of the role of NFκB in the pathophysiology of human IBD.

Challenging our understanding of the role of nuclear factor κB activation in the pathophysiology of intestinal inflammation in human inflammatory bowel disease


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  • Conflict of interest: None declared.

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