Polymorphisms of the ICAM-1 Gene Are Associated with Inflammatory Bowel Disease, Regardless of the p-ANCA Status

doi:10.1006/clim.2001.5118

Clinical Immunology

Volume 101, Issue 3, December 2001, Pages 357-360

https://doi.org/10.1006/clim.2001.5118 Get rights and content

Abstract

The intercellular adhesion molecule-1 (ICAM-1) is of paramount importance for the initiation and propagation of various inflammatory conditions. An increased frequency of allele R241 of the ICAM-1 gene was previously described in p-ANCA-negative as compared to p-ANCA-positive ulcerative colitis and vice versa in Crohn's disease. One hundred sixteen healthy unrelated controls, 121 patients with ulcerative colitis, and 96 patients with Crohn's disease were genotyped for two polymorphisms of the ICAM-1 gene (R/G241, exon 4; and K/E469, exon 6), employing dot-blot hybridization and stratified according to their p-ANCA status. When compared with the control group the frequency of the allele R241 (P = 0.024) and the heterozygous genotype R/G241, P = 0.032) were significantly increased in ulcerative colitis, whereas the homozygous genotype G/G241 was found less frequently (P = 0.022). The heterozygous genotype K/E469 was observed less frequently (P = 0.001 and 0.037, resp.) than the homozygous genotype E/E469, which was more frequent in Crohn's disease and ulcerative colitis (P = 0.002 and 0.012, respectively). Further significant differences concerning the allele or genotype distribution were not observed. After stratification for the p-ANCA status significant differences concerning the frequencies of both the R241 and the E469 alleles were not detected when p-ANCA-positive inflammatory bowel disease and p-ANCA-negative inflammatory bowel disease were compared. Ulcerative colitis and Crohn's disease are associated with polymorphisms of the ICAM-1 gene, which might therefore represent a functional candidate gene. However, the observed associations are independent of the p-ANCA status.

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Citation Excerpt :
The importance of ICAM-1 expression has been demonstrated by clinical trials of ICAM-1 antisense oligonucleotides that have shown promise in treating active CD [20, 21]. Crohn’s disease is associated with polymorphisms of the ICAM-1 gene, which might therefore represent a functional candidate gene [22]. The anti-inflammatory properties of VIP are exemplified by its ability to inhibit immune cells functions, cell migration, production of proinflammatory cytokines, chemokines, and inducible nitric oxide synthase (NOS) and to enhance the production of anti-inflammatory cytokines IL-10 and IL-1Ra [23, 24].
Stricture formation in Crohn’s disease (CD) occurs as a result of persistent intestinal inflammatory activation, which leads to enhanced adhesion molecule expression in serosal fibroblasts (SFs). Vasoactive intestinal peptide (VIP) has anti-inflammatory and immunoregulatory properties. Treatment with VIP prevents experimental CD in animal models at the clinical and pathologic levels. The present study reports the effect of VIP on the expression of intracellular adhesion molecule-1 (ICAM-1) in IL-1β-stimulated human colon SFs.
Primary human colon SFs were incubated with or without IL-1β (10 ng/mL) in the presence or absence of VIP at various concentrations (0.1 to 100 nM) for designated time. Cell surface and cytosolic ICAM-1 expression were evaluated by flow cytometry and Western blot analysis, respectively. The DNA binding capacity of NF-κB was analyzed by electrophoretic mobility shift assay. The phosphorylation of IκB-α was examined by Western blot analysis.
VIP inhibited IL-1β-induced expression of ICAM-1 in a dose-dependent manner. The IL-1β-induced ICAM-1 was also inhibited by a potent inhibitor of NF-κB, MG132. VIP also decreased IL-1β-induced NF-κB DNA binding capacity and phosphorylation of IκB-α.
VIP has an inhibitory effect on IL-1β-induced ICAM-1 expression in SFs, which may be associated with NF-κB activity. This may make VIP potentially a novel therapeutic agent for preventing stricture formation in Crohn’s disease.

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¹: To whom correspondence and reprint requests should be addressed at Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians Universität, Ziemssenstr. 1, 80336, Munich, Germany. Fax: 49 89 5160 2105. E-mail: [email protected].

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Regular ArticlePolymorphisms of the ICAM-1 Gene Are Associated with Inflammatory Bowel Disease, Regardless of the p-ANCA Status

Abstract

Immunol. Today

Free Rad. Biol. Med.

Genomics

Kidney Int.

Gastroenterology

Gastroenterology

Gastroenterology

J. Allergy Clin. Immunol.

Gastroenterology

Hum. Immunol.

Gastroenterology

Transendothelial migration

Inhibition of human mixed lymphocyte reactions by monoclonal antibodies to intercellular adhesion molecule-1 (ICAM-1)

Intercellular adhesion molecule-2, a second counter-receptor for CD11a/CD18 (leukocyte function-associated antigen-1), provides a costimulatory signal for T-cell receptor-initiated activation of human T cells

J. Immunol.

Regular Article
Polymorphisms of the ICAM-1 Gene Are Associated with Inflammatory Bowel Disease, Regardless of the p-ANCA Status