Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: presence, visualization, and significance

TY - JOUR

T1 - Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: presence, visualization, and significance

AU - Vainer, Ben

PY - 2010/8/1

Y1 - 2010/8/1

N2 - Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized clinically by episodes of bloody and pus-containing stools, abdominal discomfort, pain at defecation, and in the more severe cases even general malaise and fever. The cause of UC is unknown, but the intensive research of recent years has suggested that it involves a genetic predisposition to an uncontrolled or unbalanced immune response to luminal or epithelial antigens or to other external factors. The symptoms of UC correlate with the histological changes observed in the colonic mucosa. During active stages of the disease these changes include infiltration by significant numbers of neutrophils in the lamina propria, and these neutrophils precipitate destruction of the epithelium and hence formation of crypt abscesses and ulcerations. Intercellular adhesion molecule- 1 (ICAM-1) belongs to the family of cell adhesion molecules and through binding to b2-integrins is important for this migration of neutrophilsacross the mucosal tissue. ICAM-1 is a transmembranous glycoprotein with an immunoglobulin-like structure that is expressed primarilyby activated endothelial cells. The genefor ICAM-1 is located on chromosome 19(19p13.1-19p13.3), and ICAM-1 synthesis is stimulated by proinflammatory mediators, including tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b). Gene analyses have found polymorphisms in the gene encoding ICAM-1, indicating that changes in ICAM-1 function may be involved in the pathogenesis of UC. This review discusses the results from studies on the expression of ICAM-1 in colonic tissue from patients with UC. Various detection techniques, including enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and immunoelectron microscopy, have demonstrated that endothelial cells, macrophages, and epithelial cells in inflamed colonic tissue express ICAM-1. ICAM-1 is expressed mainly on the luminal membrane of endothelial cells, and because of this the best-described function of ICAM-1 is mediation of the firm adhesion of captured neutrophils to endothelial cells. The density of ICAM-1 expression on endothelial cells increases towards the cell boundaries, suggesting an involvement in guiding neutrophils in the right direction (haptotaxis). This effect of ICAM-1 was shown in previous in vitro studies. In the most severely inflamed cases of UC, ICAM-1 also can be demonstrated on the basal cell membrane opposite the basement membrane or the pericyte. The function of ICAM-1 in this location is not known, although it is suggested that ICAM-1 may serve as a ligand that binds neutrophils in the space just beneath the endothelial cell, allowing them to prepare for their subsequent migration across the basement membrane. Whereas the endothelial expression of ICAM- 1 is correlated with the degree of inflammation, macrophages and epithelial cells only express ICAM-1 in cases of epithelial lesions, i.e., at crypt abscesses, sites of focal epithelial damage,and ulcerations. Macrophages are phagocytic cells whose primary purpose is to remove foreign or damaged cells and cellular debris from the tissue. In UC, ICAM-1-expressing macrophages tend to accumulate next to damaged epithelium and therefore are observed around crypt abscesses and surface ulcerations. The function of macrophage ICAM-1 is unknown, but in addition to participating in the movement of macrophages across the lamina propria and aggregation of mononuclear inflammatory cells, ICAM-1 may be involved in protection of the exposed colonic tissue against the gut flora. Human nonneoplastic colonic epithelial cells do not normally express ICAM-1. However, immunohistochemistry has revealed a distinct staining on the apical cell membranes of epithelial cells located in the immediate proximity of epithelial lesions. Powerful inflammatory stimulation appears to be required for this ICAM-1 upregulation. The significance of this expression again is not known, but in vitro assays using colon cancer cell lines have suggested that it is involved in binding of neutrophils to the luminal surface of the epithelium in order to protect the bowel mucosa. Furthermore, epithelial ICAM-1 may be involved in the attraction of neutrophils and perhaps also macrophages to the damaged area, hence being pivotal for the local gut immune defense. Future research is needed to clarify the role of ICAM-1 in colonic inflammation and therefore also in order to increase our understanding of the mechanisms for development of UC. Clinical trials of the ICAM-1 antisense oligonucleotide Alicaforsen, which inhibits the synthesis of ICAM-1, have shown positive results in the treatment of patients with left-sided (distal) UC.

AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized clinically by episodes of bloody and pus-containing stools, abdominal discomfort, pain at defecation, and in the more severe cases even general malaise and fever. The cause of UC is unknown, but the intensive research of recent years has suggested that it involves a genetic predisposition to an uncontrolled or unbalanced immune response to luminal or epithelial antigens or to other external factors. The symptoms of UC correlate with the histological changes observed in the colonic mucosa. During active stages of the disease these changes include infiltration by significant numbers of neutrophils in the lamina propria, and these neutrophils precipitate destruction of the epithelium and hence formation of crypt abscesses and ulcerations. Intercellular adhesion molecule- 1 (ICAM-1) belongs to the family of cell adhesion molecules and through binding to b2-integrins is important for this migration of neutrophilsacross the mucosal tissue. ICAM-1 is a transmembranous glycoprotein with an immunoglobulin-like structure that is expressed primarilyby activated endothelial cells. The genefor ICAM-1 is located on chromosome 19(19p13.1-19p13.3), and ICAM-1 synthesis is stimulated by proinflammatory mediators, including tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b). Gene analyses have found polymorphisms in the gene encoding ICAM-1, indicating that changes in ICAM-1 function may be involved in the pathogenesis of UC. This review discusses the results from studies on the expression of ICAM-1 in colonic tissue from patients with UC. Various detection techniques, including enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and immunoelectron microscopy, have demonstrated that endothelial cells, macrophages, and epithelial cells in inflamed colonic tissue express ICAM-1. ICAM-1 is expressed mainly on the luminal membrane of endothelial cells, and because of this the best-described function of ICAM-1 is mediation of the firm adhesion of captured neutrophils to endothelial cells. The density of ICAM-1 expression on endothelial cells increases towards the cell boundaries, suggesting an involvement in guiding neutrophils in the right direction (haptotaxis). This effect of ICAM-1 was shown in previous in vitro studies. In the most severely inflamed cases of UC, ICAM-1 also can be demonstrated on the basal cell membrane opposite the basement membrane or the pericyte. The function of ICAM-1 in this location is not known, although it is suggested that ICAM-1 may serve as a ligand that binds neutrophils in the space just beneath the endothelial cell, allowing them to prepare for their subsequent migration across the basement membrane. Whereas the endothelial expression of ICAM- 1 is correlated with the degree of inflammation, macrophages and epithelial cells only express ICAM-1 in cases of epithelial lesions, i.e., at crypt abscesses, sites of focal epithelial damage,and ulcerations. Macrophages are phagocytic cells whose primary purpose is to remove foreign or damaged cells and cellular debris from the tissue. In UC, ICAM-1-expressing macrophages tend to accumulate next to damaged epithelium and therefore are observed around crypt abscesses and surface ulcerations. The function of macrophage ICAM-1 is unknown, but in addition to participating in the movement of macrophages across the lamina propria and aggregation of mononuclear inflammatory cells, ICAM-1 may be involved in protection of the exposed colonic tissue against the gut flora. Human nonneoplastic colonic epithelial cells do not normally express ICAM-1. However, immunohistochemistry has revealed a distinct staining on the apical cell membranes of epithelial cells located in the immediate proximity of epithelial lesions. Powerful inflammatory stimulation appears to be required for this ICAM-1 upregulation. The significance of this expression again is not known, but in vitro assays using colon cancer cell lines have suggested that it is involved in binding of neutrophils to the luminal surface of the epithelium in order to protect the bowel mucosa. Furthermore, epithelial ICAM-1 may be involved in the attraction of neutrophils and perhaps also macrophages to the damaged area, hence being pivotal for the local gut immune defense. Future research is needed to clarify the role of ICAM-1 in colonic inflammation and therefore also in order to increase our understanding of the mechanisms for development of UC. Clinical trials of the ICAM-1 antisense oligonucleotide Alicaforsen, which inhibits the synthesis of ICAM-1, have shown positive results in the treatment of patients with left-sided (distal) UC.

U2 - 10.1111/j.1600-0463.2010.02647.x

DO - 10.1111/j.1600-0463.2010.02647.x

M3 - Journal article

SN - 0903-465X

SP - 1

EP - 43

JO - APMIS. Supplementum

JF - APMIS. Supplementum

IS - 129

ER -