Dysregulated cytokine production by mucosal lymphocytes and macrophages has been implicated in the pathogenesis of both Crohn’s disease and ulcerative colitis, the two major forms of human inflammatory bowel disease (IBD).1 Over the past few years, various murine models of chronic intestinal inflammation resembling IBD have been discovered which have provided important clues as to the nature of this dysregulation and to its possible treatment with cytokines.2 Thus, in studies of several of the models most closely resembling Crohn’s disease it has been shown that production of large amounts of Th1-type cytokines—for example, interferon γ, by T cells is a major and essential feature of the inflammation.2 In addition, it has been shown that this disease causing Th1 cytokine response can be counteracted by induction of a suppressor response involving the generation of T cells producing Th2-type cytokines or transforming growth factor β.3Finally, it has been shown that Th1 cytokine production in these models is triggered by increased production of interleukin (IL) 12, a cytokine that plays a major role in driving T cell differentiation.3 Taken together, these data may permit the rational design of cytokine based treatment strategies for patients with IBD, and clinical trials with recombinant IL-104 and antibodies to tumour necrosis factor have already been undertaken.5 ,6

The above data predict abnormal regulation of cytokine gene transcription in patients with IBD. Thus, the focus of recent research has been on the identification of signalling pathways and transcription factors that govern cytokine gene transcription in IBD. Schreiberet al, in this issue (see page 477), report increased expression of the p65 subunit of the transcription factor NF-κB in intestinal biopsy specimens from patients with active Crohn’s disease. These results support and extend previous data indicating that concentrations of the NF-κB p65 subunit are strikingly increased in lamina propria macrophages of patients with this disease.7Furthermore, these findings are consistent with immunohistochemical data indicating increased expression of the NF-κB p65 subunit in Crohn’s disease.8

NF-κB is a pleiotropic transcriptional activator of various gene promoters for adhesion molecules and cytokines that can be induced by both cytokines and bacterial polymers.9 ,10 Many NF-κB family members are able to form homo- or heterodimers with different binding specificity toward variants of a characteristic decameric DNA recognition site (consensus sequence: GGGRNNTYCC). A wide range of stimuli promotes NF-κB nuclear translocation by a mechanism that involves the ubiquitin–proteosome pathway and IκB phosphorylation which seems to target IκB for degradation and leads to dissociation of IκB from the NF-κB complex and subsequent translocation of NF-κB to the nucleus. Given the functional importance of NF-κB in controlling transcriptional activity of promoters of various proinflammatory cytokines, the above data suggest that NF-κB plays a key role in the pathogenesis of chronic intestinal inflammation.

Inhibition of NF-κB activity has been recently suggested to be a major component of the anti-inflammatory activity of glucocorticoids, which are frequently used for treatment of chronic intestinal inflammation in humans.1 ,9 These data are consistent with Schreiber et al’s results showing downregulation of NF-κB DNA binding activity on treatment of intestinal cells with corticosteroids. Although activation of the NF-κB p65 subunit is not specific to patients with IBD, its perpetuated activation makes it an attractive target for therapeutic intervention. Thus, downregulation of NF-κB binding activity emerges as a key event in the control of chronic intestinal inflammation in humans and potential strategies to inhibit NF-κB activity more specifically are desirable. Such strategies include antioxidants proteosome inhibitors, inhibition of NF-κB by IκB expression vectors, and antisense DNA targeting of NF-κB p65.7 ,10 ,11 Thus, the above data suggest that targeting of NF-κB may be a novel molecular approach for the treatment of patients with IBD.

It is clear from various new studies that the p65 subunit of NF-κB is not the only transcription factor involved in the pathogenesis of IBD and various other regulatory proteins (for example, AP-1, NFAT and STAT proteins) are very likely to play a key role as well. It seems that we will gain new, fundamental insights into the pathogenesis, prognosis and treatment of IBD by analysing further transcriptional regulatory mechanisms in chronic intestinal inflammation. This may allow us to understand the basis for altered cytokine gene transcription in patients with IBD. Furthermore, such studies will hopefully permit the design of new treatment strategies that have added specificity but reduced toxicity compared with standard immunosuppressive therapy.