Blockade of endogenous IL-18 ameliorates TNBS-induced colitis by decreasing local TNF-alpha production in mice

Background & Aims: Interleukin (IL) 18 has proinflammatory effects. IL-18 p lays a pivotal role in Th1 responses, but its proinflammatory activities ex tend beyond Th1 cells, including macrophages and production of tumor necros is factor (TNF) alpha and IL-1 beta. IL-18 is up-regulated in colonic speci mens of patients with Crohn's disease. The goal of this study was to evalua te the role of IL-18. Methods: Activity of IL-18 was neutralized using reco mbinant human IL-18 binding protein isoform a (rhIL-18BPa) in trinitrobenze ne sulfonic acid (TNBS)-induced colitis. Results: Mice treated daily with r hIL-18BPa (8 mg/kg) had significant reductions in clinical score, body weig ht loss, and colon weight increase compared with saline-treated mice. Histo logic analysis showed that rhIL-18BPa-treated mice developed only mild coli tis without signs of ulceration, with a mean total score of 9.8 +/- 13 poin ts compared with 1.5.9 +/- 1.1 points observed in saline-treated mice with colitis. Analysis of cytokine levels in colon homogenates showed a signific ant decrease in TNF-alpha, IL-6, and IL-1 beta after rhIL-18BPa treatment b ut no effect on interferon gamma. The therapeutic potential of rhIL-18BPa t reatment was confirmed in TNBS mice that were treated only on days 8 and 9 after the start of the experiment. In these mice, significant reductions in total colitis score and colon weight were also observed. Conclusions: Thes e findings show that inhibition of rhIL-18BPa bioactivity, via rhIL-18BPa, may be beneficial for the treatment of IBD.