Integrins are important mediators of cell-laminin interactions. In the small intestinal epithelium, which consists of spatially separated proliferative and differentiated cell populations located, respectively, in the crypt and on the villus, laminins and laminin-binding integrins are differentially expressed along the cryptvillus axis. One exception to this is the integrin ␣ 6 ␤ 4 , which is thought to be ubiquitously expressed by intestinal cells. However, in this study, a re-evaluation of the ␤ 4 subunit expression with different antibodies revealed that two forms of ␤ 4 exist in the human intestinal epithelium. Furthermore, we show that differentiated enterocytes express a full-length 205-kDa ␤ 4 A subunit, whereas undifferentiated crypt cells express a novel ␤ 4 A subunit that does not contain the COOH-terminal segment of the cytoplasmic domain (␤ 4 A ctd؊ ). This new form was not found to arise from alternative ␤ 4 mRNA splicing. Moreover, we found that these two ␤ 4 A forms can associate into ␣ 6 ␤ 4 A complexes; however, the ␤ 4 A ctd؊ integrin expressed by the undifferentiated crypt cells is not functional for adhesion to laminin-5. Hence, these studies identify a novel ␣ 6 ␤ 4 A ctd؊ integrin expressed in undifferentiated intestinal crypt cells that is functionally distinct.

Laminins are a large family of heterotrimeric basement membrane molecules that mediate crucial cell functions such as adhesion, proliferation, migration, and differentiation. Up to now, three distinct laminins have been identified in the normal human small intestinal epithelium. Laminin-1 (alpha1beta1gamma1) and laminin-5 (alpha3beta3gamma2) are mainly expressed at the base of villus cells, whereas laminin-2 (alpha2beta1gamma1) is restricted to the bottom of the crypts. The expression of these molecules has not yet been studied in Crohn's disease (CD), but it could be altered, in light of the important changes occurring in the architecture of the crypt-villus axis under the active state of the disease. To test this hypothesis, the expression of laminin alpha1, alpha2, and alpha3 subunits was analyzed in control, inflamed, and corresponding uninflamed CD small intestinal specimens by indirect immunofluorescence and reverse transcriptase-polymerase chain reaction. Surprisingly, alpha1 and alpha3 remained strongly expressed by all villus cells, whereas alpha2, normally expressed in the bottom of the crypts in control and uninflamed CD specimens, was lacking in inflamed CD specimens. However, this loss of alpha2 expression was associated with a significant up-regulation of both alpha1 and alpha3 expression in the crypts of inflamed CD specimens. A significant up-regulation of the alpha1 subunit was also observed in the crypts of uninflamed CD specimens. At the transcript levels, alpha1 was found significantly higher in inflamed than uninflamed CD specimens. Taken together, these observations identify important alterations in laminin expression in the small intestine with CD and suggest that compositional changes in the epithelial basement membrane may play a role in this disease.

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