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Interleukin 15: its role in intestinal inflammation
  1. D A van Heel
  1. Correspondence to:
    Dr David van Heel
    Gastroenterology Section, Imperial College London (Hammersmith Campus), Du Cane Road, London W12 0NN, UK; d.vanheel{at}imperial.ac.uk

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Interleukin 15 may have a central role in diverse intestinal inflammatory diseases, such as coeliac disease and inflammatory bowel disease, and hence manipulation of the IL-15 pathway may have therapeutic possibilities in these conditions

The cytokine interleukin 15 (IL-15, a protein of 114 amino acids) was first discovered due to IL-2-like stimulatory actions on T cells.1,2 The heterotrimeric IL-15 receptor comprises the β and γ chains of the IL-2 receptor, with a unique α subunit. These shared receptor subunits most likely explain the similar T cell growth factor properties of both IL-2 and IL-15. Several cell types can produce IL-15, including macrophages, dendritic cells, and intestinal epithelial cells. The discovery that enterocytes can both produce and respond to IL-15,3 and that IL-15 potently stimulates intraepithelial lymphocytes,4 has focused attention on its role in intestinal inflammation. IL-15 also has a number of other activities, including recruitment and activation of T cells, maintenance of T cell memory, stimulation of proliferation and immunoglobulin synthesis by B cells, natural killer (NK) cell proliferation, activation of neutrophils, and inhibition of apoptosis. Mice with a genetically disrupted IL-15 gene (“knockout”) remain healthy under specific pathogen free conditions.5 However, they display marked reductions in numbers of thymic and peripheral NK T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes. IL-15 receptor deficient mice demonstrate a broadly similar phenotype.6 These defects are rescued in the IL-15 knockout mouse by exogenous IL-15 administration, and IL-15 is therefore critical to the development of these lymphoid lineages.

In inflammatory bowel disease, increased expression of IL-15 on peripheral blood leucocytes has been reported.7 Expression of IL-15 mRNA was found to be significantly increased in inflamed rectal mucosa of inflammatory bowel disease patients.8 IL-15 is produced by activated lamina propria macrophages in ileal biopsies from Crohn’s disease patients and colonic biopsies from ulcerative colitis patients.9 Some care does need to be taken in the interpretation of IL-15 studies, as regulation is mainly at the post-transcriptional level (rather than mRNA) and IL-15 is bioactive in both secreted and membrane-bound forms. Yoshihara and colleagues10, in a recent issue of Gut, studied dextran sulphate sodium (DSS) induced colitis, in both acute and chronic phases, in IL-15 knockout and control mice.10 In acute colitis (∼1 week DSS), IL-15 knockout mice displayed lower lethality, weight loss, and clinical and histological scores. Knockout mice had reduced lamina propria CD8+ T cells and NK cells, and lower levels of lamina propria proinflammatory cytokines (interferon γ, tumour necrosis factor α, and IL-12p40). Similar findings were seen in a chronic colitis model when DSS was given intermittently over 30 days. These data suggest targeting of IL-15 may be a novel therapeutic mechanism in inflammatory bowel disease.

In coeliac disease, IL-15 is also critical in disease pathogenesis, and its role is much better understood. IL-15 is overexpressed in both the lamina propria and intestinal epithelium of patients with active untreated coeliac disease compared with controls and gluten free diet treated coeliac patients.11 Mention and colleagues11 found that IL-15 was presented at the enterocyte cell surface, rather than being secreted in coeliac disease, suggesting a role in regulating intraepithelial lymphocytes through cell-cell contact. In ex vivo cultured duodenal biopsies, IL-15 mimics most of the epithelial modifications induced by wheat gliadin in coeliac but not in control samples.12 Recent work has suggested that a wheat gliadin peptide (A-gliadin p31–43 or p31–49), different to that recognised by T cells, might act directly to induce IL-15 production in the lamina propria and initiate epithelial apoptosis.13 This peptide induces expression of the stress molecule MICA on enterocytes, an effect mediated by IL-15.14 IL-15 also activates intraepithelial lymphocytes, including upregulation of the NKG2D receptor, which can interact with MICA thus enabling direct lymphocyte mediated cytotoxicity to enterocytes.15,16

Di Sabatino and colleagues,17 in this issue of Gut, confirm previous studies and extend our knowledge of IL-15 in coeliac disease (see page 469). IL-15 was expressed in untreated coeliac disease enterocytes and lamina propria mononuclear cells, but not in cells from treated coeliacs or healthy patients. Levels correlated with the degree of mucosal damage. Intraepithelial lymphocytes from untreated coeliac patients showed increased activation and granzyme/perforin dependent cytotoxicity against epithelial cells, and resistance to IL-15 induced apoptosis. Enhanced intraepithelial lymphocyte proliferation and apoptosis resistance might be responsible for the generation of T cell lymphoma in the coeliac disease mucosa. In contrast with previous studies (which used cell line monolayers), Sabatino et al found that IL-15 was secreted by primary human coeliac disease enterocytes as well as being presented on the cell surface. Overexpression of IL-15, specifically in intestinal epithelial cells, in a murine model has been shown to induce chronic inflammation limited to the small intestine, with a histological picture of villous atrophy and lamina propria lymphocyte infiltration.18 The lymphocyte infiltrate comprised mostly CD8+ T cells expressing an NK cell marker, which were resistant to activation induced cell death.18 Interestingly, human in vivo data has shown direct mucosal damage when wheat gliadin p31–49 peptide is instilled into the small intestine of patients with coeliac disease.19 Further research is necessary to understand the mechanisms of p31–49 signalling and its effects on intestinal mucosa, how this is linked to IL-15 production, and why these changes should only occur in coeliac disease.

A human monoclonal antibody targeting IL-15 (HuMax-IL15, Genmab) has been developed which blocks the epitope of IL-15 binding to the γ subunit of the IL-15 receptor. In a phase I/II clinical trial in rheumatoid arthritis, HuMax-IL15 was well tolerated with substantial improvements in disease activity.20 These studies suggest that manipulation of the IL-15 pathway might have therapeutic possibilities in both coeliac disease and inflammatory bowel disease. IL-15 appears to be central to coeliac disease, and probably inflammatory bowel disease pathogenesis, and greater understanding of its role is likely to generate further insights into the underlying mechanisms of intestinal inflammation.

Acknowledgments

DAvH is supported by grants from the Wellcome Trust, Coeliac UK, and Hammersmith Hospitals Charitable Trustees.

Interleukin 15 may have a central role in diverse intestinal inflammatory diseases, such as coeliac disease and inflammatory bowel disease, and hence manipulation of the IL-15 pathway may have therapeutic possibilities in these conditions

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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