IL-15 shares biological activities but no significant sequence homology with IL-2. It induces T cell recruitment to sites of inflammation, T cell proliferation, and cytokine production and rescue from apoptosis. The aim of this study was to investigate expression of IL-15 and its effects on proinflammatory cytokine production in inflammatory bowel disease (IBD). Immunohistochemistry demonstrated local IL-15 production by macrophages in inflamed mucosa from IBD patients. Isolated lamina propria mononuclear cells from these patients but not from controls produced IL-15 when stimulated with LPS or IFN-γ. Moreover, lamina propria T cells (LP-T) from IBD patients were more responsive to IL-15 as compared with controls, and IL-15 alone without a primary T cell stimulus induced IFN-γ and TNF production by isolated IBD LP-T cells, especially by LP-T cells from patients with Crohn’s disease. LP-T cells from IBD patients could induce CD40-CD40 ligand (CD40L) interaction-dependent TNF and IL-12 production by monocytes in a coculture system. This capacity of LP-T cells was strongly enhanced by preincubation in IL-15 and was the result of higher CD40L expression after culture in IL-15. These data indicate that IL-15 is overexpressed in the inflamed mucosa in IBD and that IL-15 enhances local T cell activation, proliferation, and proinflammatory cytokine production by both T cells and macrophages, the latter via a CD40-CD40L interaction-dependent mechanism. Treatment directed against IL-15 may have therapeutic potential in IBD.

Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RBhighCD4+ T cells. The results demonstrated that CD40+ and CD40L+ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RBhighCD4+ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-γ, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.

SUMMARYAn imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)-g and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RB high CD4 + T cell reconstituted SCID mice. Production of IFN-g in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4 + T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN-g and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade.

Background: The administration of indometacin to rats increases intestinal permeability and induces inflammatory pathology of the small bowel. This represents a potential model for Crohn’s disease. Aims: To analyse the pathogenic role of T cells, tumour necrosis factor and bacterial flora in indometacin‐induced changes in small bowel permeability and inflammation. Methods: Rats were given indometacin, 13 mg/kg, on day 1 and day 2. The effects of antibiotic (metronidazole, aztreonam and amoxicillin/clavulanic acid), anti‐ tumour necrosis factor and interleukin‐10 therapy were evaluated. The parameters used were weight change, serum haemoglobin, chromium‐51 ethylenediaminetetra‐acetate permeability and macro‐and microscopic score on day 5. Results in conventionally harboured rats were compared with those in T‐cell‐free rats. Additional in vitro experiments were carried out to test the effect of metronidazole on tumour necrosis factor production. Results: Indometacin administration resulted in small bowel ulcers and inflammation, independently of T cells. Metronidazole was more potent than amoxicillin/clavulanic acid and anti‐tumour necrosis factor in improving the indometacin‐induced small bowel inflammation. Only part of the efficacy was through improvement of increased intestinal permeability. Aztreonam and interleukin‐10 had no effect. Metronidazole also suppressed in vitro lipopolysaccharide‐induced tumour necrosis factor production, suggesting a therapeutic effect of this drug through the inhibition of tumour necrosis factor. Conclusions: These data implicate anaerobic bacteria and tumour necrosis factor production, but not T cells, as essential elements of the pathogenesis of indometacin‐induced small bowel inflammation. Tumour necrosis factor is also involved in the change in intestinal permeability. Metronidazole was the most efficacious drug in this model, probably because it suppressed anaerobic bacteria and directly inhibited tumour necrosis factor production.

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