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Abstract
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-y 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-alpha. 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.
Key Words
Interleukin-18 * Inflammatory bowel disease *Anti-interleukin-18 therapy * Crohn's disease
Introduction
Participation of IL-18 in the Pathogenesis of Inflammatory Bowel Disease
There is increasing evidence that an imbalance of the Th1/Th2 polarization in favor of a Th1 directed cytokine pattern is involved in the pathology of idiopathic inflammatory bowel diseases (IBD), particularly Crohn's disease (CD) [37-39]. The first evidence for a role of IL-18 in IBD came from two independent studies exploring the expression levels of IL- 18 in the course of immunoinflammatory response in CD [40, 41]. Reverse-transcriptase poly- merase chain reaction analysis demonstrated an increase in IL- 18 mRNA transcripts in mucosal tissue and lamina propria mononuclear cells (LPMCs) of infiltrated mucosal areas from CD patients as compared to tissues from ulcerative colitis (UC) patients or from non-IBD controls [40]. Whereas the non-biologically active 24-kD IL-18 precursor could be detected by Western blot in mucosal tissue samples from CD and UC patients as well as in noninflamed controls, the mature, biologically active 18-- kD form of IL,18 was abundantly detected in CD, weaker in UC but absent in non-IBD controls [40, 41 ]. Immunohistochemical...