EXPRESSION AND POLARIZATION OF INTERCELLULAR-ADHESION MOLECULE-1 ON HUMAN INTESTINAL EPITHELIA - CONSEQUENCES FOR CD11B CD18-MEDIATED INTERACTIONS WITH NEUTROPHILS/

Background: Epithelial dysfunction and patient symptoms in inflammator y intestinal diseases such as ulcerative colitis and Crohn's disease c orrelate with migration of neutrophils (PMN) across the intestinal epi thelium. Ln vitro modeling of PMN transepithelial migration has reveal ed distinct differences from transendothelial migration. By using pola rized monolayers of human intestinal epithelia (T84), PMN transepithel ial migration has been shown to be dependent on the leukocyte integrin CD11b/CD18 (Mac-1), but not on CD11a/CD18 (LFA-1). Since intercellula r adhesion molecule-1 (ICAM-1) is an important endothelial counterrece ptor for these intergrins, its expression in intestinal epithelia and role in PMN-intestinal epithelial interactions was investigated. Mater ials and Methods: A panel of antibodies against different domains of I CAM-1, polarized monolayers of human intestinal epithelia (T84), and n atural human colonic epithelia were used to examine the polarity of ep ithelial ICAM-1 surface expression and the functional role of ICAM-1 i n neutrophil-intestinal epithelial adhesive interactions. Results: Whi le no surface expression of ICAM-1 was detected on unstimulated T84 ce lls, interferon-gamma (IFN gamma) elicited a marked expression of ICAM -1 that selectively polarized to the apical epithelial membrane. Simil arly, apically restricted surface expression of ICAM-1 was detected in natural human colonic epithelium only in association with active infl ammation. With or without IFN gamma pre-exposure, physiologically dire cted (basolateral-to-apical) transepithelial migration of PMN was unaf fected by blocking monoclonal antibodies (mAbs) to ICAM-1. In contrast , PMN migration across IFN-gamma-stimulated monolayers in the reverse (apical-to-basolateral) direction was inhibited by anti-ICAM-1 antibod ies. Adhesion studies revealed that T84 cells adhered selectively to p urified CD11b/CD18 and such adherence, with or without IFN gamma pre-e xposure, was unaffected by ICAM-1 mAb. Similarly, freshly isolated epi thelial cells from inflamed human intestine bound to CD11b/CD18 in an ICAM-1-independent fashion. Conclusions: These data indicate that ICAM -1 is strictly polarized in intestinal epithelia and does not represen t a counterreceptor for neutrophil CD11b/CD18 during physiologically d irected transmigration, but may facilitate apical membrane-PMN interac tions after the arrival of PMN in the intestinal lumen.