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Am J Physiol Regul Integr Comp Physiol 281: R1264-R1273, 2001;
0363-6119/01 $5.00
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Vol. 281, Issue 4, R1264-R1273, October 2001

Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production

Britta Siegmund1, Giamila Fantuzzi1, Florian Rieder2, Fabia Gamboni-Robertson3, Hans-Anton Lehr4, Gunther Hartmann2, Charles A. Dinarello1, Stefan Endres2, and Andreas Eigler2

Departments of 1 Medicine and 3 Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80206; 2 Division of Clinical Pharmacology, Medizinische Klinik Innenstadt, Klinikum of the Ludwig-Maximilians-University Munich, 80336 Munich; and 4 Institute of Pathology, University of Mainz, 55131 Mainz, Germany

Interleukin (IL)-18, initially described as interferon (IFN)-gamma -inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-gamma concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-alpha , IL-18, and IFN-gamma production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-gamma synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

inflammation; cytokines; antibodies; in vivo animal models


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