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Uncoupling the p38 MAPK kinase in IBD: a double edged sword?
  1. V Arulampalam,
  2. S Pettersson
  1. Microciology and Tumorbiology Centre, Karolinska Institute, Stockholm, Sweden
  1. Correspondence to:
    Professor Sven Pettersson, Centre for Genomics Research, Karolinska Institute, Doktorsringen 2P, 171 77 Stockholm, Sweden,
    sven.pettersson{at}cgr.ki.se

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Dichotomal effects of specific p38 mitogen activated protein kinase (MAPK) inhibition in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice

Ulcerative colitis (UC) and Crohn's disease (CD), the most predominant manifestations of inflammatory bowel diseases (IBD), are accelerating major health problems. Although the aetiology of IBD remains elusive, a great deal of work has been carried out in successfully identifying some of the pathological and clinical profiles that are perturbed in these patients. This has led to the description of some of the molecular mechanisms that may underlie the idiopathic inflammation encountered in IBD. More recently, gene families and clusters which may be implicated in the onset of IBD, albeit in a limited manner, have been discovered.

Cytokines such as interleukin (IL)-1, IL-6, tumour necrosis factor α (TNF-α), and interferon γ among others, have been shown to maintain the highly chronic inflamed state of the bowel, if not actually causing the onset of this condition. Hence one (major) effort to uncouple the vicious circle and to combat this disease has been to eliminate or diminish the effects of these cytokines. The use of molecules blocking cytokine receptor interactions, by disrupting the means of cytokine activity (for example, inhibiting nuclear factor κB using antisense molecules), is well documented. Taken together, there is an increasing demand to further understand the signalling mechanisms of various cytokines.

In most instances, the mitogen activated protein kinase (MAPK) family of enzymes are involved in transducing the cytokine signal within the epithelial cell of the gut mucosa. These enzymes are predominantly serine/threonine kinases and are activated via phosphorylation of these moieties in a well regulated cascade, leading to activation of specific transcription factors and subsequent target genes. Nevertheless, a linear cascade of kinase activation appears unlikely as other “peripheral” effectors most likely will also be induced and should therefore be included in any therapeutic regime directed towards cytokine signalling pathways.

A number of such anti-inflammatory therapies undergoing pharmacological and preclinical studies have targeted numerous serine/threonine kinases. Of these kinases, activation of p38 MAPK by a plethora of extracellular stimuli, including cellular stress, osmotic shock, and proinflammatory cytokines, is well documented. A number of p38 kinase inhibitors have been identified, including a dominant negative p38 molecule, but harnessing use of small molecule inhibitors appears to be the most promising in the present clinical setting.

Initially identified as an inhibitor of cytokine release (for example, TNF), the pyridinilimidazole compound SB203580 was later identified as an inhibitor of p38 kinase activity. This and other p38 inhibitors (for example, CNI-1493, ML3163) have been previously shown to be efficient in reducing the severity of inflammatory disease, including endotoxin induced mortality and collagen induced arthritis in mouse models. In this issue of Gut, ten Hove and colleagues1 have queried the efficacy of this compound in blocking trinitrobenzene sulphonic acid (TNBS) induced colitis [see page 507]. The results, although not entirely unexpected, have posed some interesting questions regarding p38 function, especially in IBD. Briefly, limited reduction in IL-12 cytokine production was observed, with no discernible loss of TNF expression in colon homogenates. Furthermore, in SB 203580 treated TNBS mice, wasting was more significant but colonic weight was higher despite a decrease in cell numbers in colonic lymph nodes compared with controls. Thus one of the observed effects may be to intervene on cell fate, be it to stop cell growth or induce apoptosis. Hence in this instance it appears that although some of the inflammatory agents are affected, thus in part abrogating the inflammatory process, it is not sufficient to completely ameliorate inflammation by p38 inactivation.

A number of explanations for the lack in efficacy have been suggested. One explanation assumes that “disease” initiating signalling pathways, bypassing the p38 block, precede p38 activation. Another invokes the function of upstream activators which can regulate inflammation in a p38 independent manner in TNBS induced colitis.

The precise nature of colitis induction by TNBS is unknown and thus other “inflammatory pathways” could also be activated by such an agent. To date, at least five isoforms of p38, two of which are ubiquitous, have been identified. Although regarded as a selective inhibitor of p38, extensive studies have not revealed a pan isoform inhibition through SB 203580. Hence some of the effects seen in this study may be due to the nature of the inhibitor, primarily those pertaining to antiproliferation and cell cycle regulation. The results presented by ten Hove et al are therefore of general interest and increased research activity in this area is certainly much needed.

One other alternative explanation is the less studied role of p38 induced downregulation of signalling. In the absence of an active p38 MAPK, negative feedback regulation of inflammatory signalling may well be hampered. In these instances, not only intercellular (as discussed by ten Hove and colleagues1) but also intracellular cross talk may be affected. At present the nature of the latter remains to be elucidated but given the importance of switch off mechanisms, this field of enquiry will no doubt receive warranted attention in the near future.

IBD being multifactorial speaks for a complexity that transcends the perturbation of just one (p38) among many kinases. Hence in the gut, merely inactivating p38 may not be sufficient to ameliorate the inflammatory process. Alternatively, p38 may still have a kinase independent role (as postulated for Jak2), involved in recruitment and structural modification. This function may contribute to the enhanced severity of the disease in this study as p38 itself is still phosphorylated.

The work presented by ten Howe et al in this issue of Gut1 illuminates the complexity of signalling mechanisms that must be unravelled before we can obtain a coherent picture of diseases such as IBD. Having acquired this information, but only then, can the development of new drugs be expected. Until then the question as to whether deactivating p38 suffices in ameliorating (TNBS induced) colitis remains to be answered.

Dichotomal effects of specific p38 mitogen activated protein kinase (MAPK) inhibition in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice

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