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

Interleukin (IL)-18, initially described as interferon (IFN)-gamma -inducin g factor, is expressed in the inflamed mucosa of patients with Crohn's dise ase. To investigate the role of IL-18 in intestinal inflammation, the effec t 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 re sponse of DSS, levels of colonic IL-18 increased parallel with clinical wor sening. 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 an d C57BL/6 mice. Colon shortening following DSS-induced colitis was partiall y prevented in the treatment groups. In the colon tissue homogenates, IFN-g amma concentrations were lower in the anti-IL-18-treated DSS-fed mice compa red with untreated DSS-fed mice. This suppressive effect of anti-IL-18 admi nistered in vivo was also observed on spontaneous tumor necrosis factor-alp ha, 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 t hat IL-18 is a pivotal mediator in experimental colitis.