[Crohn's disease].

IL-18 is among the cytokines responsible for immune-mediated pathologies and is probably one of the factors that contribute to the pathogenesis of autoimmune diseases. Identification of the causes of uncontrolled IL-18 production and activity in autoimmunity would allow for novel therapeutic targets to effectively block autoimmune activation and inhibit concomitant tissue damage. IL-18 is produced mainly by monocytes/macrophages in response to stimuli of viral/bacterial origin, its production being therefore one of the effects of innate immunity initiated by host-pathogen interaction. In this review, we summarise the evidence supporting both the effector and the pathogenic role of IL-18 in autoimmunity, and propose that the disturbed mechanism of innate immunity, resulting from macrophage activation through innate immunity receptors (TLR/IL-1R family), may be the basis of pathologically high levels of IL-18 production and activation. Unravelling the mechanisms of IL-18 production and activity in autoimmune diseases will allow the identification of targets for more effective therapeutic intervention.

IL-18 in autoimmunity: review

IL18 was mapped to 11q22.2-22.3 in 1998. Owing to interleukin (IL)-18's important and novel role in immunomodulation, the gene itself has been subject to scrutiny, with the aim of discovering variants that may impact on disease susceptibility and/or progression. Despite being sequenced numerous times in different populations, no non-synonymous variants have been found. However, a number of polymorphisms within the proximal promoter have been verified that may interfere with transcription-factor-binding sites. Much of the subsequent association analyses have centred on these variants, but have yielded no consistent results, despite numerous different study populations being genotyped. IL18 has recently been resequenced in its entirety, enabling the tagging-single-nucleotide polymorphism (tSNP) methodology to be adopted. This approach has yielded interesting results, with genetic variation being shown to affect protein levels, and risk. This review aims to compile and reflect on the association data of interest published to date, with a focus on the diseases related to aberrant inflammatory control.

Interleukin-18 genetics and inflammatory disease susceptibility.

The vast majority of peripheral T cells exist as resting lymphocytes until a signal for activation has been received. In response to antigen, this activation involves ligation of the T-cell receptor (TCR) and signal transmission through the CD3 complex, which then initiates a cascade of intracellular events that lead to the expression of genes used in T-cell activation. T-cell activation also requires soluble mediators in the form of cytokines and chemokines that regulate the process in both positive and negative ways, and costimulatory signals received in conjunction with TCR/CD3 signaling are important in the activation of T cells. Unlike T cells in other peripheral immune compartments, small and large intestinal intraepithelial lymphocytes (IELs) bear some but not all properties of activated T cells, suggesting that they constitute a large population of 'partially activated' effector cells. Thus, regulation of the IEL activation process must be held in tight check, yet it must be ready to respond to foreign antigen rapidly and effectively. We discuss how costimulatory molecules may hold the key to controlling IEL activation through a multiphase process beginning with cells that have already entered into the early stage of activation.

/pdf/t-cell-activation-in-the-intestinal-mucosa-28rmx9r61w.pdf

T-cell activation in the intestinal mucosa

Inappropriate responses to normal intestinal bacteria may be involved in the development of Inflammatory Bowel Diseases (IBD, e.g. Crohn's Disease (CD), Ulcerative Colitis (UC)) and variations in the host genome may mediate this process. IL-10 gene-deficient (Il10
 -/-
 ) mice develop CD-like colitis mainly in the colon, in part due to inappropriate responses to normal intestinal bacteria including Enterococcus strains, and have therefore been used as an animal model of CD. Comprehensive characterization of changes in cecum gene expression levels associated with inflammation in the Il10
 -/-
 mouse model has recently been reported. Our aim was to characterize changes in colonic gene expression levels in Il10
 -/-
 and C57BL/6J (C57; control) mice resulting from oral bacterial inoculation with 12 Enterococcus faecalis and faecium (EF) strains isolated from calves or poultry, complex intestinal flora (CIF) collected from healthy control mice, or a mixture of the two (EF·CIF). We investigated two hypotheses: (1) that oral inoculation of Il10
 -/-
 mice would result in greater and more consistent intestinal inflammation than that observed in Il10
 -/-
 mice not receiving this inoculation, and (2) that this inflammation would be associated with changes in colon gene expression levels similar to those previously observed in human studies, and these mice would therefore be an appropriate model for human CD. At 12 weeks of age, total RNA extracted from intact colon was hybridized to Agilent 44 k mouse arrays. Differentially expressed genes were identified using linear models for microarray analysis (Bioconductor), and these genes were clustered using GeneSpring GX and Ingenuity Pathways Analysis software. Intestinal inflammation was increased in Il10
 -/-
 mice as a result of inoculation, with the strongest effect being in the EF and EF·CIF groups. Genes differentially expressed in Il10
 -/-
 mice as a result of EF or EF·CIF inoculation were associated with the following pathways: inflammatory disease (111 genes differentially expressed), immune response (209 genes), antigen presentation (11 genes, particularly major histocompatability complex Class II), fatty acid metabolism (30 genes) and detoxification (31 genes). Our results suggest that colonic inflammation in Il10
 -/-
 mice inoculated with solutions containing Enterococcus strains is associated with gene expression changes similar to those of human IBD, specifically CD, and that with the EF·CIF inoculum in particular this is an appropriate model to investigate food-gene interactions relevant to human CD.

/pdf/changes-in-colon-gene-expression-associated-with-increased-5gljtvshrt.pdf

Changes in colon gene expression associated with increased colon inflammation in interleukin-10 gene-deficient mice inoculated with Enterococcus species

Background: An increased expression of interleukin-18 (IL-18), a proinflammatory cytokine inducing interferon-γ, has been found in Crohn's disease (CD). In the IL-18 gene, several partly functional relevant polymorphisms are known. This study sought to investigate associations of IL-18 polymorphisms in inflammatory bowel disease and CD according to CARD15/NOD2 mutation status and clinical phenotypes. Methods: The IL-18 polymorphisms -607, -137, and the third position of codon 35 (c35/3) were genotyped in 210 patients with CD, 140 patients with ulcerative colitis, and 265 healthy controls using polymerase chain reaction and restriction fragment length polymorphism analysis. Results: Frequencies of alleles and genotypes of the 3 polymorphisms and of the respective haplotypes and diplotypes displayed no significant differences between the whole groups of patients with CD and ulcerative colitis, respectively, compared with the controls. After stratification of patients with CD for CARD14/NOD2 status, significant associations of genotypes -137 CC (P = 0.018) and c35/3 CC (P = 0.010) and of the diptotype 2-2 (P = 0.018) were found in cases carrying CARD15/NOD2 mutations. Associations of genotypes -137 GG (P = 0.015) and c35/3 AA (P = (1.030) with colonic disease only in cases positive for CARD14/NOD2 mutations and of the genotype -607 AA (P = 0.007) with fistulas in cases negative for CARD15/NOD2 mutations were observed. Conclusions: In this study, significant differences of several genotypes and diplotypes within the IL-18 gene in CD depending on CARD15/NOD2 status have been found. In context with an increased expression of IL-18 in CD, it remains to be shown whether the expression of IL-18 is influenced by CARD15/NOD2 mutation status.

Association of polymorphisms in the interleukin-18 gene in patients with Crohn's disease depending on the CARD15/NOD2 genotype

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Association of polymorphisms in the interleukin-18 gene in patients with Crohn's disease depending on the CARD15/NOD2 genotype