There is considerable evidence that inflammatory bowel disease (IBD), and a variety of other inflammatory disorders, reflect an excessive Th1 response. However, as we shall see below, a number of studies depleting the known members of this inflammatory cascade have reported some “residual” pathology and suggested that “other mediators” may also be involved. A study by Chikano and colleagues1 suggests that interleukin 18 (IL-18) may be one of the villains.

The characteristic cytokine produced by Th1 cells, interferon γ (IFN-γ), has been shown to play a role in the pathogenesis of a number of autoimmune and inflammatory disorders2 and has long been suspected of a role in IBD. Administration of IFN-γ produces small intestinal pathology in mice3 ,4 while elevated IFN-γ expression and increased numbers of IFN-γ secreting cells have been reported in human IBD and are a feature of many of the murine models of IBD.5 ,6 The importance of IFN-γ in such situations has been highlighted by the ability of in vivo depletion of this cytokine to ameliorate disease in a number of models of gastrointestinal pathology. However, more recent studies in a variety of models of IBD have revealed some inconsistencies.5 ,7 Some reports have suggested IFN-γ knockout (KO) CD4⁺ T cells are incapable of inducing colitis and wasting, others have reported comparable disease in IFN-γ^null and wild type (WT) animals, while a recent study7 suggests that IFN-γ KO T cells cause less severe pathology than that seen with WT cells. The study of Chikano and colleagues1 in last month's issue ofGut indicates that the pathological effects of combined IL-12 and IL-18 administration are similarly IFN-γ dependent as they are not apparent in IFN-γ KO animals (seeGut 2000;47:779–86). However, the mechanism of the effects of interleukin 12 (IL-12) are not clear as they could not be mimicked by administration of exogenous IFN-γ alone. It therefore seems likely that the IFN-γ dependent effects of co-administration of IL-12 and IL-18 require the presence of additional mediators.

IL-12 production by activated macrophages and dendritic cells is one of the most important factors influencing polarisation of precursor T cells towards a Th1-type.8 This cytokine can cause enteropathy when administered to mice,4 is upregulated in human IBD, and its depletion prevents pathology in the murine TNBS colitis model.5 ,6 While the current study1did not find intestinal pathology when IL-12 alone was administered, it is consistent with earlier findings using in vivo antibody depletion of IL-12 or animals deficient in the IL-12 signalling cascade molecule Stat-4, demonstrating that IL-12 is important, although not essential, for the development of colitis and that IL-12 dependent pathology may not require the presence of IFN-γ.9 The authors of this study proposed that the milder colitis that can develop in the absence of IL-12 may implicate other molecules, such as IL-18, which they had not investigated.

The recently discovered proinflammatory IL-1 family member IL-18 is produced by monocytes/macrophages, including liver Kupffer cells, and keratinocytes and has been shown to potentiate the effects of lipopolysaccharide and IL-12.1 ,10 IL-18 synergises with IL-12 in the induction of T cell priming, by sustaining the expression of the IL-12 receptor subunit IL-12Rβ2, as well as production of the macrophage activating cytokine IFN-γ. This follows upregulation of IL-18R by IL-12, specifically on Th1 cells, suggesting that IL-18 is an important component of T cell priming leading to Th1 development. IL-18 increases IFN-γ expression by stimulating activation of the transcription factors nuclear factor κΒ and AP-1.10Furthermore, IL-18 has been reported to be upregulated in IBD patients11 and a number of other inflammatory conditions. Thus the results of Chikano and colleagues1 are consistent with the suggested role of Th1 cells/IFN-γ/IL-12 in enteropathy.5 ,6 However, this cytokine has also recently been shown to upregulate the Th2 polarising cytokine IL-13 and to potentiate Th2 responses in a number of models.12 ,13While Th1 and Th2 responses are usually considered to be mutually opposing aspects of T cell function, the recent description of apparently Th2 mediated IBD5 indicates that Th2-type responses may contribute to intestinal pathology and it will be important to investigate the role of IL-18 in this context.

Tumour necrosis factor α (TNF-α) is one of the important effector molecules associated with the inflammatory cascade induced by activation of Th1 cells in a variety of autoimmune/inflammatory disorders and more recently in Th2 mediated pathology.5TNF-α has also received much attention in IBD.5 ,6Increased TNF-α production has been reported in Crohn's patients and is also a feature of all of the murine models of IBD.4 ,5Anti-TNF-α has been shown to reduce pathology and mortality in some of these systems5 ,6 while TNF-α causes significant enteropathy when administered to normal animals.3 ,4These studies have culminated in the successful use of anti-TNF-α therapy in Crohn's disease.5 ,6 Thus TNF-α would have been a likely candidate as one of the “additional mediators” involved in the IL-12/18 induced, IFN-γ dependent pathology described by Chikano and colleagues. It is therefore somewhat surprising that Chikano et al did not find a role for this molecule in the IL-12+IL-18 induced pathology they describe.

Another mediator usually associated with the Th1 mediated, TNF-α associated inflammatory cascade is nitric oxide (NO). The role of NO in inflammatory conditions (particularly in the gastrointestinal tract) remains controversial and the debate is confounded by the multiple effects of this molecule on functions ranging from blood supply to direct damage via induction of apoptosis. However, NO appears to play a crucial role in a number of pathological conditions, including diabetes mellitus, graft versus host disease, rheumatoid arthritis, and several models of enteropathy.14

Thus Chikano et al show that IL-18 in combination with IL-12 can induce marked intestinal and hepatic pathology in an IFN-γ dependent manner but that the majority of these effects are TNF-α and NO independent. Furthermore, while their studies demonstrating an absence of pathology when IFN-γ is administered to mice contradict earlier work3 ,4 they imply that the IFN-γ dependent effects of IL-12/18 treatment are not mediated directly. These studies have important implications if considering IL-18 as a therapeutic target as this may be inappropriate in situations where TNF-α has a proven role, yet it may provide an adjunct or combination therapy where TNF-α depletion alone has proved unsuccessful. However, before clinical applications are seriously considered, a number of issues will require clarification. It will be important to determine the mechanisms of the putative indirect effects via other receptor-ligand pairs which have yet to be investigated. In this respect the use of tissue/cell specific KOs of IFN-γ/IFN-γR will be invaluable in determining the sources and targets of IL-12, IL-18, and IFN-γ and this will also aid identification of the “additional mediators” involved. Finally, the effects of depleting IL-18 (either with antibodies, soluble receptors, competitors, or via genetic manipulation) in models of IBD, or of IL-18 administration in Th2 models of IBD or in conjunction with Th2 cytokines will be essential.