HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 23, 16948-16958, June 8, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/23/16948    most recent M700158200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Charrier, L. Articles by Merlin, D. Search for Related Content PubMed PubMed Citation Articles by Charrier, L. Articles by Merlin, D. Social Bookmarking                      What's this?

ADAM-15/Metargidin Mediates Homotypic Aggregation of Human T Lymphocytes and Heterotypic Interactions of T Lymphocytes with Intestinal Epithelial Cells^*

Laetitia Charrier¹, Yutao Yan², Hang Thi Thu Nguyen, Guillaume Dalmasso, Christian L. Laboisse, Andrew T. Gewirtz^¶, Shanthi V. Sitaraman, and Didier Merlin

From the Department of Medicine, Division of Digestive Diseases, and ^¶Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322 and INSERM, U539, Nantes F-44035, France

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- 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.

Received for publication, January 5, 2007 , and in revised form, March 30, 2007.

^* This work was supported in part by National Institutes of Health Grants R24-DK064399, DK061941, DK071594 (to D. M.), DK061417 (to A. T. G.), and DK55850 (to S. V. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Recipient of a research fellowship award from the Crohn and Colitis Foundation of America.

¹ Supported by The Crohn and Colitis Foundation of America and Elvin and Janet Price. To whom correspondence should be addressed: Dept. of Medicine, Division of Digestive Diseases Emory University, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-6234; Fax: 404-727-5767; E-mail: lcharri{at}emory.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. Charrier-Hisamuddin, C. L. Laboisse, and D. Merlin ADAM-15: a metalloprotease that mediates inflammation FASEB J, March 1, 2008; 22(3): 641 - 653. [Abstract] [Full Text] [PDF]

				J. L. Zhong, Z. Poghosyan, C. J. Pennington, X. Scott, M. M. Handsley, A. Warn, J. Gavrilovic, K. Honert, A. Kruger, P. N. Span, et al. Distinct Functions of Natural ADAM-15 Cytoplasmic Domain Variants in Human Mammary Carcinoma Mol. Cancer Res., March 1, 2008; 6(3): 383 - 394. [Abstract] [Full Text] [PDF]