Immunomodulation in IBD Animal Models

Interleukin (IL)-18 is a cytokine with a broad array of effector functions, the most prominent of which is to act synergistically with IL-12 in interferon-Á production and the induction of a strong T-helper-1-mediated immune response. In addition, IL-18 also upregulates the production of proinflammatory cytokines such as IL-1 and tumor necrosis factor-·. Analysis of IL-18-deficient mice revealed an important role of IL-18 in the activation of macrophages and natural killer cells in the context of infection with intracellular bacteria or parasites. In humans, it was reported that IL-18 is elevated at sites of inflammation in inflammatory bowel disease (IBD), particularly in Crohn’s disease, suggesting a possible role for IL-18 in the development and persistence of IBD. In this review we summarize recent findings on the functional role of IL-18 in the pathogenesis of colitis with a special focus on murine models of IBD. The neutralizing mouse anti-mouse IL-18 antibodies generated in our group should facilitate the evaluation of the efficiency of therapeutic blockade of endogenous IL-18 in chronic mouse models of colitis besides the use of recombinant forms of the inhibitory IL-18-binding protein. Copyright © 2003 S. Karger AG, Basel Introduction The cytokine interleukin (IL)-18 was initially identified as a potent interferon-Á (IFN-Á)-inducing factor [1]. It was purified from the livers of mice treated with Propionibacterium acnes and subsequently challenged with lipopolysaccharide (LPS) to induce a toxic shock syndrome [2]. IL-18 is synthesized as a bioinactive 24-kD precursor protein that is cleaved by IL-1ß-converting enzyme (ICE, caspase-1), leading to the release of the biologically active 18-kD protein. However, alternative caspase-1 independent processing by caspase-3 or -4, or proteinase-3 has also been postulated [3]. Production of IL-18 mRNA and the bioactive protein has been demonstrated for a wide range of cells including Kupffer cells, macrophages, T cells, B cells, osteoblasts, keratinocytes, dendritic cells, astrocytes and microglia [4, 5]. Besides this production by immune cells, expression of bioactive IL-18 has also been detected in nonimmune cells such as intestinal and airway epithelial cells [6, 7]. The most prominent function of IL-18 is to induce IFN-Á production from T, B and natural killer (NK) cells, in particular in the presence of IL-12 [2, 8]. In vitro, treatment of T cells with both IL-12 and IL-18 leads to strong IFN-Á production, but these T cells do not develop into T-helper-1 (Th1) cells without concomitant T-cell receptor engagement [8]. Stimulation of T cells with anti-CD3 and IL-18 results in IFN-Á production which can be abro-