Abstract

Intestinal epithelial cells (IEC) play an immunoregulatory role in the intestine. This role involves cell-cell interactions with intraepithelial lymphocytes that may also play a role in some enteropathies. The discovery of the RGD motif-containing Protein ADAM-15 (a disintegrin and metalloprotease-15) raises the question of its involvement in these cell-cell interactions. Cell adhesion assays were performed using the Jurkat E6.1 T cell line as a model of T lymphocytes and Caco2-BBE monolayers as a model of intestinal epithelia. Our results show that an anti-ADAM-15 ectodomain antibody inhibited the attachment of Jurkat cells on Caco2-BBE monolayers. Overexpression of ADAM-15 in Caco2-BBE cells enhanced Jurkat cell binding, and overexpression of ADAM-15 in Jurkat cells enhanced their aggregation. Mutagenesis experiments showed that both the mutation of ADAM-15 RGD domain or the deletion of its cytoplasmic tail decreased these cell-cell interactions. Moreover, wound-healing experiments showed that epithelial ADAM-15-mediated Jurkat cell adhesion to Caco2-BBE cells enhances the mechanisms of wound repair. We also found that ADAM-15-mediated aggregation of Jurkat cells increases the expression of tumor necrosis factor-alpha mRNA. These results demonstrate the following: 1) ADAM-15 is involved in heterotypic adhesion of intraepithelial lymphocytes to IEC as well as in homotypic aggregation of T cells; 2) both the RGD motif and the cytoplasmic tail of ADAM-15 are involved for these cell-cell interactions; and 3) ADAM-15-mediated cell-cell interactions are involved in mechanisms of epithelial restitution and production of pro-inflammatory mediators. Altogether these findings point to ADAM-15 as a possible therapeutic target for prevention of inappropriate T cell activation involved in some pathologies.

Highlights

  • A few molecular interactions have been identified that are involved in the specific retention of lymphocytes in intestinal epithelia

  • We previously reported that human Intestinal epithelial cells (IEC) express ADAM-15 on the cell membrane surface [38], and very recently we found that during inflammatory bowel disease (IBD) ADAM-15 is strongly up-regulated and ADAM-15-positive IEC are in close contact with ␣5␤1 integrin-positive leukocytes [39]

  • These findings suggest a role for ADAM-15 in leukocyte transepithelial migration that occurs during IBD

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Summary

Introduction

A few molecular interactions have been identified that are involved in the specific retention of lymphocytes in intestinal epithelia. Cell-cell and cell-fusion protein adhesion assays showed that ␣E␤7 integrin expressed on T cells mediates T lymphocytes/IEC adhesion via E-cadherin [2, 21,22,23,24,25,26]. We previously reported that human IEC express ADAM-15 on the cell membrane surface [38], and very recently we found that during IBD ADAM-15 is strongly up-regulated and ADAM-15-positive IEC are in close contact with ␣5␤1 integrin-positive leukocytes [39]. These findings suggest a role for ADAM-15 in leukocyte transepithelial migration that occurs during IBD. Our aim was to investigate whether ADAM-15 participates in cell-cell interactions between IEC and T lymphocytes

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