Proinflammatory and antitumor properties of interleukin-18 in the gastrointestinal tract
Introduction
The transformation of CD4+ helper T cells into Th1 cells (producing IL-2 and IFN-γ) or Th2 cells (producing IL-4, IL-5, IL-6, IL-10 and IL-13) depends on their mode of priming by antigen presenting cells (APC). In addition to expressing MHC molecules loading antigenic peptides, and co-stimulating molecules, APC produce cytokines that induce CD4+ T cell differentiation. IL-12 and IL-4 induce differentiation of naive T cells toward Th1 and Th2 lymphocytes, respectively [1]. Recently, a cytokine has been isolated and cloned from activated macrophages and Kupffer cells [2], [3]. This cytokine, named interleukin-18, is produced by APC and presents pleiotropic activities ranging from development of Th1 cells, enhancement of the cytotoxic potential of effector cells, and proinflammatory properties [4]. Recent reports on IL-18 in the field of cancer and inflammation suggest that inappropriate IL-18 production contributes to the pathogenesis of these diseases and may influence the clinical outcome of patients.
Section snippets
IL-18 structure and biological properties
Interleukin-18 (IL-18), previously named Interferon-γ-inducing factor (IGIF), was purified and cloned in 1995 from the liver of mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide to induce toxic shock [2]. In man, the IL-18 gene is located on chromosome 11q22 and encodes a 193 amino acid precursor protein [5]. IL-18 has structural similarities with the IL-1 family of proteins, with 12% and 19% of amino acid sequence homologies with IL-1α and IL-1β, respectively
IL-18 and intestinal mucosal integrity
The immunohistochemistry method used to assess IL-18 production in gut does not discriminate between the three forms of IL-18 (immature, mature, and degraded forms). Most of the IL-18 signal observed in normal gut mucosa is probably related to detection of the proIL-18 form, as proIL-18 is the sole form detected by a Western blot method [17], [18]. ICE transcripts and proteins are detected throughout the gastrointestinal tract, suggesting that large amounts of mature IL-18 can be rapidly
Antitumor activity of IL-18: implications in colonic cancer
IL-18, in combination with IL-12, induces Th1 cell differentiation, enhances cell-mediated cytotoxicity and promotes the inflammatory process. This suggests that IL-18 may play an important role in antitumor immunity.
A local Th1 polarization is correlated with a good prognosis in several cancers [24], [25], as IFN-γ, a Th1 cytokine induced by IL-18, promotes immune recognition of tumor cells by enhancing MHC molecules and antigen processing and stimulates cytotoxicity of NK cells, T lymphocytes
IL-18 as a proinflammatory cytokine: implications in Crohn's disease
The potential of IL-18 to contribute to inflammatory and autoimmune diseases is suggested by its capacity to induce proinflammatory cytokines, chemokines, nitric oxide, and prostaglandins. This is amplified by IL-18-induced IFN-γ production, which in turn activates macrophages. Many lines of evidence suggest that IL-18 is critical for the initiation and maintenance of insulin-dependent diabetes mellitus [36], [37], multiple sclerosis [38], [39], and rheumatoid arthritis [40], [41], and may be
Acknowledgements
The authors would like to thank Marion Delauneux from DAKO Corporation for her expert advice on antibody staining.
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