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Objective: Population-specific differences in the genetic susceptibility to inflammatory bowel disease (IBD) are indicated by the fact that Crohn's disease (CD) in Japanese patients does not have any of the common CARD15 variants that are associated with CD in Caucasians. Recently, the disease-causing mutation in the IBD5 haplotype was identified. The TC haplotype, composed of L503F in SLC22A4 and -207G/C in SLC22A5 promoters, was reported to alter the function of the organic cation transporter and to be associated with CD in Caucasians. To determine whether the TC haplotype is also associated with IBD in a Japanese population, we genotyped L503F and -207G/C variants in Japanese subjects. Furthermore, we also performed a case-control association study with all representative single nucleotide polymorphisms (SNPs) in IBD5 using previous information of linkage disequilibrium extension reported in Japanese patients to determine whether there were variants in IBD5 specifically associated with IBD in Japanese patients., Material and Methods: A total of 758 Japanese individuals, 241 patients with CD, 247 patients with ulcerative colitis (UC) and 270 healthy controls, were analyzed in this study. Genotyping for SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis., Results: We found L503F and -207G/C to be very rare (<1% frequency) in CD, UC and HC in the Japanese population. Furthermore, we also found that none of the representative SNPs in IBD5 was associated with CD or UC in the Japanese subjects., Conclusions: In contrast to Caucasians, IBD5 is not a major component of the susceptibility to IBD in the Japanese population.

Telomerase acitivity can be induced in human B lymphocytes by in vitro stimulation of their antigen receptors. To determine whether telomerase activity is induced in vivo, we analyzed telomerase activity in B lymphocytes from the mesenteric lymph nodes of patients with inflammatory bowel disease (IBD), whose lymph nodes are well known to be strongly stimulated, and from those of noninflamed controls. Seven IBD patients and 4 noninflamed controls were enrolled. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications. The mesenteric lymph nodes from patients with IBD had stronger telomerase activity than those from controls or peripheral mononuclear cells. Isolation of CD19+ B lymphocytes from these lymph nodes showed that this strong activity resides in this lymphocytes subpopulation. This study provides the evidence that telomerase activity is induced in human B lymphocytes in human inflammatory disease.

The aim of the present study is to clarify in situ expression of platelet-derived growth factor (PDGF) and its receptors in different phases of inflammatory bowel disease (IBD). Tissues samples were obtained from 20 patients with ulcerative colitis (UC) and 29 with Crohn's disease (CD) at surgery. In situ hybridization and immunohistochemistry on frozen sections were performed for PDGF-A and -B and its alpha and beta receptors (alphaR and betaR). The area of active inflammation was infiltrated by abundant polymorphonuclear and mononuclear leukocytes, of which the latter expressed mRNA and proteins of PDGF-A, -B, and -alphaR and mRNA for PDGF-betaR. The area of active fibrosis, characterized by activated fibroblasts/ myofibroblasts, was juxtaposed to ulceration, which is induced as a repair process to tissue destruction. In these areas, activated fibroblasts/myofibroblasts were positive for mRNA and protein of PDGF-A, -B, -alphaR, and -betaR. The expression of PDGF-A, -B, and -alphaR declined significantly in the scar area. Our results suggest that PDGF is not only important as an inducer of fibrosis in the repair phase but also it is involved in the active inflammatory phase possibly as a chemoattractant for mononuclear inflammatory cells.

Aims: Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease., Methods and Results: Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn's disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels., Conclusions: Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 transmit a same signal needed for growth and activation in granulocytes and macrophages, because these receptors utilize a common beta chain. Little is known about growth factors for intestinal myeloid cells in lesions of inflammatory bowel disease (IBD)., Aim: To find out whether GM-CSF is produced by the intestinal cells in IBD patients and controls., Methods: We measured levels of GM-CSF, tumor necrosis factor (TNF), and IL-3 in the media of organ culture and lamina propria mononuclear cells (LPMCs) culture of colonic mucosa from the patients with IBD. Next, we have investigated GM-CSF production of colonic epithelial cell lines., Results: Spontaneous secretion of GM-CSF was increased in inflamed mucosa, while secretion of IL-3 was not detected. Release of GM-CSF was enhanced in LPMCs from inflamed mucosa. Mucosal GM-CSF production was correlated to TNF-alpha production. Colonic epithelial cell line and T cell produced GM-CSF with superantigen stimulation., Conclusion: We revealed pivotal production of GM-CSF but not IL-3 in intestinal lesion of IBD. Increased secretion of GM-CSF might lead to chronic gut inflammation., (Copyright 2001 S. Karger AG, Basel)

Endothelial leucocyte adhesion molecule-1 (ELAM-1) is a rapidly inducible adhesion molecule for neutrophils in vascular endothelial cells. We investigated its immunohistochemical localization in 17 cases of inflammatory bowel disease. ELAM-1 was preferentially expressed in venules in actively inflamed mucosa and granulation tissue. Most capillaries were negative for ELAM-1. In areas with mild inflammation its expression diminished markedly and in normal mucosa of the colon and small intestine its expression was sparse. Electron microscopically, venules in active inflammation had swollen endothelial cells with well-developed rough endoplasmic reticulum. Immunoelectron microscopy revealed ELAM-1 localization along the luminal plasma membrane and in rough endoplasmic reticulum and round granules, findings suggestive of active production in endothelial cells. Furthermore, exocytosis of immunoreactive substance into the lumen was confirmed. Our study suggests that venules in actively inflamed area play an important role in eliciting and/or maintaining acute inflammatory processes by active permeation of neutrophils from the blood stream into the tissue, and that ELAM-1 may be a secretory protein as well as a transmembrane receptor protein.

Background Although thiopurines have a proven role in maintenance therapy for Crohn's disease, an alternative therapy is needed for patients intolerant or resistant to thiopurines. Aim To evaluate the effectiveness of home enteral nutrition as a maintenance therapy regimen in which half of the daily calorie requirement is provided by an elemental diet and the remaining half by a free diet. We refer to this home enteral nutrition therapy as ‘half elemental diet’. Methods Between 2002 and 2005, 51 patients in remission from two hospitals were randomly assigned to a half elemental diet group ( n = 26) or a free diet group ( n = 25). The primary outcome measure of this study was the occurrence of relapse over the 2-year period. Results The relapse rate in the half elemental diet group was significantly lower [34.6% vs. 64.0%; multivariate hazard ratio 0.40 (95% CI: 0.16–0.98)] than that in the free diet group after a mean follow-up of 11.9 months. Compliance was similar in the two groups. No adverse event occurred in any of the patients throughout the study. Conclusion This randomized-controlled trial shows the effectiveness of an half elemental diet, which is a promising maintenance therapy for Crohn's disease patients. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) representing both Crohn's disease and ulcerative colitis are characterized by chronic activation of macrophages. Natural resistance-associated macrophage protein 1 (NRAMP1) gene regulates macrophage activation of antimicrobial activity and has many pleiotropic effects on macrophage functions. To explore the role of the NRAMP1 gene in IBD susceptibility, we examined the promoter sequence of the NRAMP1 gene whose polymorphisms have been reported to influence the transcriptional activity of the NRAMP1 gene. One novel allele (allele 7) and two previously reported alleles (alleles 2 and 3) have been determined in a Japanese population. We investigated the association of IBD with these three alleles. The allele frequency of allele 7 was significantly higher in patients with Crohn's disease (11.1%) and ulcerative colitis (11.2%) than those in the healthy control group (4.5%) (Pc =0.015, Pc =0.018, respectively). Therefore, our findings suggest that the novel promoter polymorphism of the NRAMP1 gene may influence susceptibility to IBD in the Japanese population. [ABSTRACT FROM AUTHOR]