Elevated serum concentrations of soluble selectin and immunoglobulin type adhesion molecules in patients with inflammatory bowel disease

  • Michael Göke
  • Jörg C. Hoffmann
  • Jörg Evers
  • Hartmut Krüger
  • Michael P. Manns
Alimentary Tract


Adhesion molecules mediate the extravasation of leukocytes and their accumulation in inflamed tissues. In the present study, serum concentrations of the selectin (sP- and sE-selectin) and immunoglobulin supergene family (sICAM-1 and sVCAM-1) of adhesion molecules were measured in 93 patients with inflammatory bowel disease (Crohn's disease,n=65; ulcerative colitis,n=28) and 58 age-matched normal controls. sP-selectin serum concentrations (mean ±SEM ng/ml) of patients with Crohn's disease (399 ±33 ng/ml) and ulcerative colitis (385 ± 42 ng/ml) were increased (P=0.0067 andP=0.0193, respectively) compared to controls (251±33 ng/ml). In contrast, E-selectin serum levels of patients with Crohn's disease (58±5 ng/ml) and ulcerative colitis (64±12 ng/ml) were not significantly higher than those of controls (53±5 ng/ml). sICAM-1 serum concentrations of patients with Crohn's disease (420±19 ng/ml) and those with ulcerative colitis (375±40 ng/ml) were elevated (P=0.0001 andP=0.0473, respectively) compared to controls (197±8 ng/ml). Further, sVCAM-1 levels of patients with Crohn's disease (664±43 ng/ml) and ulcerative colitis (963±162 ng/ml) were increased (P=0.0222 andP=0.0121, respectively) compared to controls (510±31 ng/ml). With few exceptions, serum levels of soluble adhesion molecules were not significantly correlated to disease activity indices or disease localization. Elevated circulating selectin and immunoglobulin supergene type adhesion molecules may compete with membrane-bound forms for their cognate ligands and thereby limit the rolling and stable adhesion of leukocytes.

Key words

P-selectin E-selectin VCAM-1 ICAM-1 Crohn's disease ulcerative colitis 


  1. 1.
    Springer TA. Adhesion receptors of the immune system. Nature 1990;346:425–434.PubMedCrossRefGoogle Scholar
  2. 2.
    Butcher EC. Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity. Cell 1991;67:1033–1036.PubMedCrossRefGoogle Scholar
  3. 3.
    Lasky LA. Selectins: Interpreters of cell-specific carbohydrate information during inflammation. Science 1992;258:964–969.PubMedCrossRefGoogle Scholar
  4. 4.
    Dustin ML, Rothlein R, Bhan AK, et al. Induction by IL 1 and interferon-γ: Tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol 1986;137:245–254.PubMedGoogle Scholar
  5. 5.
    Pober JS, Gimbrone Jr MA, Lapierre LA, et al. Overlapping patterns of activation of endothelial cells by interleukin 1, tumor necrosis factor, and immune interferon. J Immunol 1986; 137:1893–1896.PubMedGoogle Scholar
  6. 6.
    Marlin SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte function-associated antigen 1 (LFA-1). Cell 1987;51:813–819.PubMedCrossRefGoogle Scholar
  7. 7.
    Smith CW, Marlin SD, Rothlein R et al. Cooperative interactions of LFA-1 and Mac-1 with intercellular adhesion molecule-1 in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest 1989;83:2008–2017.PubMedCrossRefGoogle Scholar
  8. 8.
    Wegner CD, Gundel RH, Reilly P, et al. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science 1990;247:456–459.PubMedCrossRefGoogle Scholar
  9. 9.
    Sano H, Nakagawa N, Nakajima H, et al. Role of vascular cell adhesion molecule-1 and platelet-activating factor in selective eosinophil migration across vascular endothelial cells. Int Arch Allergy Immunol 1995;107:533–540.PubMedCrossRefGoogle Scholar
  10. 10.
    Rice GE, Bevilacqua MP. An inducible endothelial cell surface glycoprotein mediates melanoma adhesion. Science 1989;246: 1303–1306.PubMedCrossRefGoogle Scholar
  11. 11.
    Osborn L, Hession C, Tizard R, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes. Cell 1989;59:1203–1211.PubMedCrossRefGoogle Scholar
  12. 12.
    Elices MJ, Osborn L, Takada Y, et al. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 1990;60: 577–584.PubMedCrossRefGoogle Scholar
  13. 13.
    Pulido R, Elices MJ, Campanero MR, et al. Functional evidence for three distinct and independently inhibitable adhesion activities mediated by the human integrin VLA-4. J Biol Chem 1991;266:10241–10245.PubMedGoogle Scholar
  14. 14.
    Van Dinther-Janssen ACHM, Horst E, Koopman G, et al. The VLA-4/VCAM-1 pathway is involved in lymphocyte adhesion to endothelium in rheumatoid synovium. J Immunol 1991;147:4207–4210.PubMedGoogle Scholar
  15. 15.
    Bevilacqua MP, Pober JS, Mendrick DL, et al. Identification of an inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci USA 1987;84:9238–9242.PubMedCrossRefGoogle Scholar
  16. 16.
    Bevilacqua MP, Stengelin S, Gimbrone Jr MA, et al. Endothelial leukocyte adhesion molecule 1: An inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science 1989;243:1160–1165.PubMedCrossRefGoogle Scholar
  17. 17.
    McEver RP, Martin MN. A monoclonal antibody to a membrane glycoprotein binds only to activated platelets. J Biol Chem 1984;259:9799–9804.PubMedGoogle Scholar
  18. 18.
    Johnston GI, Kurosky A, McEver RP. Structural and biosynthetic studies of the granule membrane protein, GMP-140, from human platelets and endothelial cells. J Biol Chem 1989;264:1816–1823.PubMedGoogle Scholar
  19. 19.
    Picker LJ, Kishimoto TK, Smith CW, et al. ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 1991;349:796–799.PubMedCrossRefGoogle Scholar
  20. 20.
    Shimizu Y, Shaw S, Graber N, et al. Activation-independent binding of human memory T cells to adhesion molecule ELAM-1. Nature 1991;349:799–802.PubMedCrossRefGoogle Scholar
  21. 21.
    Phillips ML, Nudelman E, Gaeta FCA, et al. ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. Science 1990;250:1130–1132.PubMedCrossRefGoogle Scholar
  22. 22.
    Walz G, Aruffo A, Kolanus W, et al. Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells. Science 1990;250:1132–1135.PubMedCrossRefGoogle Scholar
  23. 23.
    Steegmaier M, Levinovitz A, Isenmann S, et al. The E-selectinligand ESL-1 is a variant of a receptor for fibroblast growth factor. Nature 1995;373:615–620.PubMedCrossRefGoogle Scholar
  24. 24.
    Sako D, Chang XJ, Barone KM, et al. Expression cloning of a functional glycoprotein ligand for P-selectin. Cell 1993;75:1179–1186.PubMedCrossRefGoogle Scholar
  25. 25.
    Johnston GI, Bliss GA, Newman PJ, et al. Structure of the human gene encoding granule membrane protein-140, a member of the selectin family of adhesion receptors for leukocytes. J Biol Chem 1990;265:21 381–21 385.Google Scholar
  26. 26.
    Larsen E, Celi A, Gilbert GE, et al. PADGEM protein: A receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 1989;59:305–312.PubMedCrossRefGoogle Scholar
  27. 27.
    Hamburger SA, McEver RP. GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood 1990;75:550–554.PubMedGoogle Scholar
  28. 28.
    Geng JG, Bevilacqua MP, Moore KL, et al. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature 1990;343:757–760.PubMedCrossRefGoogle Scholar
  29. 29.
    Polley MJ, Phillips ML, Wayner E, et al. CD62 and endothelial cell-leukocyte adhesion molecule 1 (ELAM-1) recognize the same carbohydrate ligand, sialyl-Lewis x. Proc Natl Acad Sci USA 1991;88:6224–6228.PubMedCrossRefGoogle Scholar
  30. 30.
    Tedder TF, Steeber DA, Chen A, et al. The selectins: Vascular adhesion molecules. FASEB J 1995;9:866–873.PubMedGoogle Scholar
  31. 31.
    Lasky LA. Selectin-carbohydrate interactions and the initiation of the inflammatory response. Annu Rev Biochem 1995;64:113–139.PubMedCrossRefGoogle Scholar
  32. 32.
    Ley K, Tedder TF. Leukocyte interactions with vascular endothelium. New insights into selectin-mediated attachment and rolling. J Immunol 1995;155:525–528.PubMedGoogle Scholar
  33. 33.
    Rothlein R, Mainolfi EA, Czajkowski M, et al. A form of circulating ICAM-1 in human serum. J Immunol 1991;147:3788–3793.PubMedGoogle Scholar
  34. 34.
    Seth R, Raymond FD, Makgoba MW. Circulating ICAM-1 isoforms: Diagnostic prospects for inflammatory and immune disorders. Lancet 1991;338:83–84.PubMedCrossRefGoogle Scholar
  35. 35.
    Lobb R, Chi-Rosso G, Leone D, et al. Expression and functional characterization of a soluble form of vascular cell adhesion molecule 1. Biochem Biophys Res Commun 1991;178:1498–1504.PubMedCrossRefGoogle Scholar
  36. 36.
    Lobb RR, Chi-Rosso G, Leone DR, et al. Expression and functional characterization of a soluble form of endothelial-leukocyte adhesion molecule 1. J Immunol 1991;147:124–129.PubMedGoogle Scholar
  37. 37.
    Katayama M, Handa M, Ambo H, et al. A monoclonal antibodybased enzyme immunoassay for human GMP-140/P-selectin. J Immunol Methods 1992;153:41–48.PubMedCrossRefGoogle Scholar
  38. 38.
    Dunlop LC, Skinner MP, Bendall LJ, et al. Characterization of GMP-140 (P-selectin) as a circulating plasma protein. J Exp Med 1992;175:1147–1150.PubMedCrossRefGoogle Scholar
  39. 39.
    Gearing AJW, Hemingway I, Pigott R, et al. Soloble forms of vascular adhesion molecules, E-selectin, ICAM-1 and VCAM-1: Pathological significance. Am NY Acad Sci 1992;667:324–331.CrossRefGoogle Scholar
  40. 40.
    Gearing AJH, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993;14:506–512.PubMedCrossRefGoogle Scholar
  41. 41.
    Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 1976;70:439–444.PubMedGoogle Scholar
  42. 42.
    Van Hees PAM, van Elteren PH, van Lier HJJ, et al. An index of inflammatory activity in patients with Crohn's disease. Gut 1980;21:279–286.PubMedCrossRefGoogle Scholar
  43. 43.
    Gomes P, Du Boulay C, Smith CL, et al. Relationship between disease activity indices and colonoscopic findings in patients with colonic inflammatory bowel disease. Gut 1986;27:92–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Hoffmann JC, Dengler TJ, Knolle PA, et al. A soluble form of the adhesion receptor CD58 is present in human body fluids. Eur J Immunol 1993;23:3003–3010.PubMedCrossRefGoogle Scholar
  45. 45.
    Wellicome SM, Kapahi P, Mason JC, et al. Detection of a circulating form of vascular cell adhesion molecule-1: Raised levels in rheumatoid arthritis and systemic lupus erythematosus. Clin Exp Immunol 1993;92:412–418.PubMedGoogle Scholar
  46. 46.
    Katayama M, Handa M, Araki Y, et al. Soluble P-selectin is present in normal circulation and its plasma level is elevated in patients with thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Br J Haematol 1993;84:702–710.PubMedCrossRefGoogle Scholar
  47. 47.
    Dippold W, Wittig B, Schwaeble W, et al. Expression of intercellular adhesion molecule 1 (ICAM-1, CD54) in colonic epithelial cells. Gut 1993;34:1593–1597.PubMedCrossRefGoogle Scholar
  48. 48.
    Nielsen OH, Langholz E, Hendel J, et al. Circulating soluble intercellular adhesion molecule-1 (sICAM-1) in active inflammatory bowel disease. Dig Dis Sci 1994;39:1818–1923.CrossRefGoogle Scholar
  49. 49.
    Jones SC, Banks RE, Haidar A, et al. Adhesion molecules in inflammatory bowel disease. Gut 1995;36:724–730.PubMedCrossRefGoogle Scholar
  50. 50.
    Koizumi M, King N, Lobb R, et al. Expression of vascular adhesion molecules in inflammatory bowel disease. Gastroenterology 1992;103:840–847.PubMedGoogle Scholar
  51. 51.
    Ohtani H, Nakamura S, Watanabe Y, et al. Light and electron microscopic immunolocalization of endothelial leucocyte adhesion molecule-1 in inflammatory bowel disease. Virchows Arch A Pathol Anat Histopathol 1992;420:403–409.PubMedCrossRefGoogle Scholar
  52. 52.
    Schürmann GM, Bishop AE, Facer P, et al. Increased expression of cell adhesion molecule P-selectin in active inflammatory bowel disease. Gut 1995;36:411–418.PubMedCrossRefGoogle Scholar
  53. 53.
    Collins CE, Rampton DS. Platelet dysfunction: A new dimension in inflammatory bowel disease. Gut 1995;36:5–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Wong CS, Gamble JR, Skinner MP, et al. Adhesion protein GMP140 inhibits superoxide anion release by human neutrophils. Proc Natl Acad Sci USA 1991;88:2397–2401.PubMedCrossRefGoogle Scholar
  55. 55.
    Podolsky DK, Lobb R, King N, et al. Attenuation of colitis in the Cotton-top tamarin by anti-α4 integrin monoclonal antibody. J Clin Invest 1993;92:372–380.PubMedCrossRefGoogle Scholar
  56. 56.
    Arber N, Berliner S, Hallak A, et al. Increased leucocyte adhesiveness/aggregation is a most useful indicator of disease activity in patients with inflammatory bowel disease. Gut 1995;37:77–80.PubMedCrossRefGoogle Scholar
  57. 57.
    Pooley N, Ghosh L. Up-regulation of E-selectin and intercellular adhesion molecule-1 differs between Crohn's disease and ulcerative colitis. Dig Dis Sci 1995;40:219–225.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1997

Authors and Affiliations

  • Michael Göke
    • 1
  • Jörg C. Hoffmann
    • 2
  • Jörg Evers
    • 1
  • Hartmut Krüger
    • 2
  • Michael P. Manns
    • 1
  1. 1.Department of Gastroenterology and HepatologyMedizinische Hochschule HannoverHannoverGermany
  2. 2.Department of RheumatologyMedizinische Hochschule HannoverHannoverGermany

Personalised recommendations