Involvement of interleukin 18 in Crohn's disease: evidence fromin vitroanalysis of human gut inflammatory cells and from experimental colitis models

Abstract

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.

An angiotensin II receptor antagonist reduces inflammatory parameters in two models of colitis

“…In this model the over expression of IL-18 protein was decreased in those animals treated with Valsartan. IL-18 has been shown to be increased and play an important role in the primary stages of inflammation in DSS colitis, and its inhibition with a recombinant IL-18 binding protein was able to attenuate intestinal damage in both this model [35], as well as the TNBS model [36]. In the present study valsartan treatment caused an upregulation in the gene expression of IL-10, a cytokine which is known to be therapeutic in both the DSS and TNBS models of colitis.…”

Remission-inducing effect of anti-TNF monoclonal antibody in TNBS colitis

“…IL-18 is a macrophage-derived cytokine and a potent inducer of IFN-␥ for intestinal lymphocytes. 19 Anti-IL-18 mAb was shown to result in a dramatic attenuation of TNBS colitis. 19 IL-18 mRNA in anti-TNF-treated TNBS colitis mice was also significantly reduced (Fig.…”

Plasma Interleukin-18 Levels in Hemodialysis Patients: Increased by Dialysis Process and Association with Interleukin-6 and Tumor Necrotic Factor-α

“…in many infl ammatory diseases, including rheumatoid arthritis [4] , Crohn's disease [5] , and atherosclerosis [6] . Patients who underwent hemodialysis (HD) were also in a state of chronic infl ammation [7][8][9] .…”