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Microbe-host interactions in the alimentary tract: the gateway to understanding inflammatory bowel disease
  1. N FRENCH,
  1. Centre For Genomics Research, Karolinska Institutet
  2. Berzelius väg 37, 171 77 Stockholm, Sweden
  1. S Pettersson. Email:Sven.Pettersson{at}

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Inflammatory bowel disease (IBD), typified by ulcerative colitis and Crohn's disease, has an aetiology that appears to possess both genetic and environmental components. A number of mouse models of intestinal inflammation have been identified. For example, the interleukin (IL)-10 knockout mouse develops inflammation that is histologically similar to Crohn's disease1 while the IL-2 and T cell receptor α knockout animals develop inflammation that resembles ulcerative colitis.2 3 Together with other genetic mutant mouse models that develop IBD, these reports strongly support the view that genetic defects can predispose an individual to IBD. To our knowledge, however, the genetic defect models that have been described to date do not develop overt IBD if they are kept in a pathogen free environment, implying that the mucosal microflora plays a role in the initiation and/or perpetuation of the disease process. Despite the uncertain aetiology of IBD, the symptoms of the disease are associated with overproduction of proinflammatory cytokines and a commonly held view is that the disease is primarily a consequence of a deregulated adaptive immune system.

Transcriptional control of many inflammatory cytokines (including IL-4, tumour necrosis factor α (TNF-α), etc) is mediated by the transcription factor NF-κB,4 a key component in the inducible transcription of proinflammatory cytokines. NF-κB is normally retained in the cytoplasm by binding to its inhibitor protein, IκB, which masks the NF-κB nuclear localisation signal (NLS).5 A broad range of external stimuli that lead to activation of NF-κB set off signalling cascades that ultimately converge on the IκB kinase (IKK) complex.6 Activated IKK specifically and directly phosphorylates IκB and this phosphorylation event targets IκB for degradation.5 As a consequence, NF-κB NLS is uncovered and nuclear translocation occurs. External stimuli that can activate NF-κB include IL-1β, TNF-α, and bacterial lipopolysaccharide (LPS), the major constituent of Gram negative bacterial cell walls. Until recently the eukaryotic receptor for LPS remained elusive but a huge advance in this field was made when a mammalian homologue of Drosophila Toll was shown to transduce signals in response to LPS dependent activation.7 In Drosophila, the Toll receptor has been shown to participate in both dorso-ventral patterning during embryonic development and in the immune response of adult flies.8 Toll signals to theDrosophila homologue of NF-κB,dorsal, viacactus (an IκB homologue) which activates genes that encode antimicrobial peptides. Six published mammalian toll-like receptors (TLRs) have been reported9 10 and they all contain repeated leucine rich motifs in their extracellular domains. They are thought to act as pattern recognition receptors (PRRs) that, by definition, are receptors that recognise invariant pathogen associated molecular patterns.11 Other PRRs of the mammalian innate immune system include the mannose receptor12 and scavenger receptors.13Interestingly, the cytoplasmic domain of the TLRs display a high degree of homology to the signalling domain of the IL-1 receptor and is referred to as the Toll homology domain.10 Signal transduction molecules that are required for IL-1 dependent NF-κB activation are also used for TLR signalling to NF-κB.14TLRs therefore appear to constitute part of a phylogenetically ancient defence mechanism that is referred to as the innate immune system. The innate immune process initiates recognition of invading microbial organisms (be they pathogenic or non-pathogenic).

The critical role of NF-κB in the control of innate immunity suggests that microbes with the capacity to colonise the host are likely to be armed with mechanisms that can subvert the activation of innate responses. Very little, if anything, is known about these regulatory properties but regulation of TLR expression or modulation of their signal transduction pathways may be two possible mechanisms of action. One particular bacterial pathogen, Yersinia pestis, together with Y pseudotuberculosis and Y enterocolitica, can infect a host without inducing a robust immune response. All three strains harbour a virulence plasmid that encodes a type III secretion system and this mediates secretion of different Yersinia effector proteins (Yops). On cell contact, Yops are translocated into eukaryotic cells15 16 where they interfere with cellular responses and ensure bacterial adherence. For example, through the action of YopH, Yersinia targets focal adhesion structures and can resist phagocytosis by macrophages.17 18 Another effector protein, YopJ, abrogates signalling pathways that lead to activation of NF-κB, the cyclic AMP response element binding protein (CREB), and activator protein 1 (AP-1) 19-22 and it has recently been shown to have substrate specificity for several mitogen activated protein (MAP) kinase kinases.23 MAP kinase kinases (MAPKKs) are a conserved family of proteins that phosphorylate and activate specific downstream MAP kinases that in turn activate a variety of immediate early response genes critical for the production of cytokines and growth factors.24 The target of YopJ in signalling pathways that activate NF-κB is IKKβ and it appears to block the ability of IKK to phosphorylate IκB.23 As IKK is the converging point for the majority of extracellular stimuli that activate NF-κB (including signals from the TLRs),Yersinia has evolved an extremely efficient mechanism to counter inflammatory responses.

As mentioned above, YopJ can also interfere with CREB signalling, presumably by incapacitating the upstream MAPKKs that signal via p38 mitogen activated protein kinase (MAPK) through to CREB. One well documented target for CREB is AP-1, a transcription factor that is intimately involved in cell growth. YopJ can consequently affect the mitogenic potential of infected cells and is capable of inhibiting LPS induced clonal expansion in primary B lymphocytes (Meijeret al, unpublished observations). The observation that p38 MAPK appears to be required for the development and activity of Th1 cells25 highlights an additional inhibitory potential of YopJ. Therefore, it seems that YopJ can counter inflammatory responses at multiple levels by interfering with both innate and adaptive immune responses.

A question arises as to whether the effects attributed to YopJ are unique to Yersinia or can be thought of as a more generalised evolutionary trait of bacteria. Considering the huge bacterial load that the gastrointestinal tract receives—in a human individual this amounts to 2 kg of bacteria—the potential to activate TLRs (and thus NF-κB) is manifest. It is tempting to speculate that YopJ-like proteins (or proteins that can perform the same role as YopJ) have evolved in all commensal bacteria to help counter the induction of widespread inflammatory responses. Database comparisons of YopJ protein sequence do indeed uncover a number of homologous proteins. The capacity to modulate inflammatory responses in animals or to interfere with hypersensitive responses in plants may therefore be evolutionarily conserved.26-28

As well as having evolved mechanisms to control mammalian cell transcription via the type III secretion system, bacteria use additional tricks to modulate an inflammatory response. For example, the endotoxic activity of LPS resides in the lipid A portion of the molecule and alterations in the structure of lipid A can change the biological activity of LPS.29 Differences in LPS structure are presumably detected by TLRs that signal induction of distinct transcriptional responses. One could therefore simplistically envisage the commensal milieu as bacterial colonies that express endotoxin displaying a low biological activity with respect to inflammatory induction. An alternative and intriguing view is that different expression patterns of TLRs on different mucosal surfaces determine the inflammatory response. Indeed, recent studies have shown that bladder and intestinal epithelial cells display different TLR expression patterns (Richter-Dahlfors, unpublished observations) and this may go some way to explaining why certain uropathogenicEscherichia coli strains exist as commensal flora in the gut. Other bacterial surface molecules/structures such as intimin and fimbriae can also influence host responses.30 31 A picture is emerging whereby a combination of both structural determinants and secreted bacterial effector molecules define precise host signalling cascades that trigger specific transcriptional responses and ultimately the extent of an inflammatory reaction. The intense research in this field will undoubtedly provide a greater understanding as to why certain bacteria are inflammation inducing pathogens, others are pathogens that evade inflammatory reactions, but the great majority exist in a peaceful symbiotic relationship with the host.

Research efforts that have been brought to bear on adaptive immunity over the past 20 years have revealed a number of dysfuntional adaptive immune mechanisms that can predispose towards IBD. Good correlations have also been drawn between patients suffering from different forms of IBD and upregulated Th1 or Th2 driven immune responses.32 33 Innate immunity is now recognised as the bridge between the recognition of an invading microbial infection and mounting of an efficient adaptive immune reaction that can overcome the infection. It will surely not be long before genetic defects in innate immune mechanisms join those of its adaptive counterpart as predisposing factors in IBD. Although provocative, one could therefore view the upregulated Th1/Th2 responses in certain patients as anormal adaptive immune response (albeit a destructive one) to a deregulated innate immune system. If we are to understand pathological processes within the alimentary tract (typified by IBD) it is clear that the fundamental aspects of microbe-host interactions need to be examined in greater detail. By doing so, we will find novel therapeutic approaches in the treatment of chronic inflammation.


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  • Leading articles express the views of the author and not those of the editor and editorial board.

  • Abbreviations used in this paper:
    inflammatory bowel disease
    IκB kinase
    toll-like receptor
    pattern recognition receptor
    mitogen activated protein
    mitogen activated protein kinase
    nuclear localisation signal
    tumour necrosis factor α
    Yersinia effector proteins
    cyclic AMP response element binding protein
    activator protein 1

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