Article Text

Activation of NFκB in inflammatory bowel disease
  1. R M SCHMID,
  2. G ADLER
  1. Department of Internal Medicine I,
  2. University of Ulm, Ulm, Germany
  3. Department of Paediatrics,
  4. University of Ulm, Ulm, Germany
  1. Dr Schmid, Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.
  1. Department of Internal Medicine I,
  2. University of Ulm, Ulm, Germany
  3. Department of Paediatrics,
  4. University of Ulm, Ulm, Germany
  1. Dr Schmid, Department of Internal Medicine I, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany.
  3. J HAMPE
  1. First Medical Department,
  2. Christian Albrechts University,
  3. Schittenhelmstrasse 12,
  4. 24105 Kiel, Germany
  5. email: s.schreiber{at}

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    Editor,—In their recent paper (Gut1998;42:477–84) Schreiber and coworkers demonstrated that RelA (p65) is present in nuclear extracts of biopsy specimens or lamina propria mononuclear cells from patients with active inflammatory bowel disease (IBD). Furthermore, they show NFκB binding activity and a corresponding decrease in IκBα in lamina propria mononuclear cells treated with lipopolysaccharide (LPS). In contrast, treatment with dexamethasone prevented LPS induced nuclear translocation of NFκB due to persistence of IκBα. The authors conclude from these data that corticosteroids inhibit NFκB activation in vitro by stabilising the cytosolic inhibitor IκBα against activation induced degradation.

    Firstly, this conclusion cannot be drawn from the data presented in the paper. Secondly, their conclusion contradicts a number of previously published observations.

    Two models of corticosteroid mediated NFκB inhibition have been proposed. The first proposes that down modulation of κB driven genes results from a physical interaction between the glucocorticoid receptor and the RelA (p65) subunit. Negative cross-talk between the glucocorticoid receptor and RelA is due to direct interaction via the Rel homology domain of RelA and the DNA binding domain of the glucocorticoid receptor in combination with interference by the transactivation domain of RelA with the transcriptional activity of the glucocorticoid receptor.1-5

    The second model proposes that the inhibitory effect of glucocorticoids is mediated by the induction of the IκBα protein, which traps activated NFκB in inactive cytoplasmic complexes. It has been shown that dexamethasone induces transcriptional upregulation of the IκBα gene, although a glucocorticoid responsive element has not been identified in the IκBα promoter. Thus, in the presence of dexamethasone, released NFκB quickly reassociates with newly synthesised IκBα which results in notably reduced amounts of NFκB that translocates to the nucleus.6-7

    So far there is no evidence that steroids stabilise IκBα. However, we have recently shown that sulphasalazine interferes with IκBα phosphorylation and proteasome dependent degradation of IκBα in vitro.8 Therefore, the available data point towards different levels of interference with NFκB activation by sulphasalazine and corticosteroids.



    Editor,—We appreciate the comments by Schmid and colleagues which address important aspects of the cellular mechanisms involved in the in vitro regulation of NFκB activation. Our sequential publications in Gut have tackled the clinical importance of the in vivo activation of the proinflammatory transcription factor NFκB in inflammatory bowel disease (IBD). We have also shown the importance of human granulocytes in primary cultures as specific contributors to this process.1-1 1-2These studies were not designed to investigate the cellular mechanism of steroid action in the NFκB system, but rather to look at important clinical aspects of NFκB activation and steroid treatment in Crohn’s disease.

    An important anti-inflammatory mechanism in steroid action is the inhibition of NFκB activation.1-3 1-4 It has been suggested that this mechanism involves the induction of IκBα expression, the stabilisation of IκBα (resulting in sequestration of NFκB in the cytoplasm) and protein–protein interactions between NFκB and the glucocorticoid receptor, leading to inhibition of transactivation.1-5

    The exact mechanisms leading to the steroid induced persistence of IκBα protein are not established. Although some experiments have shown upregulation of the expression of IκBα by steroids, as those cited by Schmid et al, these findings have not been reproduced in more recent studies.1-6-1-8 In addition, the glucocorticoid-like immunosuppressive effect of oestrogen as well as other steroid hormones is also attributed to stabilisation of the IκBα protein as a result of inhibition of IκBα degradation.1-9 The kinetics of IκBα degradation in human granulocytes are very rapid and steroid induced protection of the IκBα protein is seen within minutes. One may therefore speculate how much induction of expression and how much stabilisation against degradation may contribute to the rapid time course in granulocytes. The relative contribution of these mechanisms to the clinical efficacy of steroids in inhibiting activation of NFκB needs to be evaluated in future studies.

    Taken together, the understanding of the role of IκBα in steroid induced suppression of NFκB activation is hampered by conflicting findings which may partly result from the stimulatory conditions chosen. The choice of the cell system (i.e. epithelial carcinoma cell lines which often have an altered IκBα/NFκB system versus primary cells1-10) may also confound these data.

    Schmid et al also discuss the mechanism of the anti-inflammatory action of sulpha- salazine.1-11 They propose that treatment with sulphasalazine results in the inhibition of IκBα degradation, whereas aminosalicylates (5-ASA) or sulphapyridin have no effect on NFκB activation.1-11 The authors’ findings, which have been obtained in colonic carcinoma (SW620) and Jurkat T cell lines, add an important aspect to the mechanisms of action of anti-inflammatory drugs in IBD but also underline the importance of the experimental system investigated as discussed earlier. In other systems (e.g. primary monocyte cultures) aminosalicylates also seemed to inhibit the activation of NFκB via inhibition of IκBα degradation.1-12-1-18

    Activation of NFκB may be a central element in the pathophysiology of Crohn’s disease. Inhibition of NFκB activation offers an attractive hypothesis for the action of numerous drugs with clinically relevant effects in IBD. The exact mechanisms involved have yet to be determined in the relevant cell systems and in further ex vivo studies using affected tissues of diseased patients.


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