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INFLAMMATION/IMMUNITY/MEDIATORS

Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia

¹Institut National de la Santé et de la Recherche Médicale (INSERM) ERI-21/EA 4319, ²Department of Gastroenterology, ³Laboratory of Clinical and Experimental Pathology and ⁶Human Tissue Biobank/CRB INSERM, Pasteur Hospital, and Faculty of Medicine, University of Nice Sophia Antipolis, Nice, France; ⁴INSERM U843, Robert Debré Hospital, University of Paris 7, Paris, France; and ⁵INSERM U631, CNRS UMR 6102, Centre d'Immunologie de Marseille-Luminy, University of Aix Marseille, Marseille, France

Submitted 31 October 2008 ; accepted in final form 12 March 2009

The acute phase of Crohn's disease (CD) is characterized by a large afflux of polymorphonuclear leukocytes (PMNL) into the mucosa and by the release of TNF-. Conversion of inactive TNF- into an active form requires the cleavage of a transmembrane TNF- precursor by the TNF--converting enzyme (ADAM17), a protease mainly regulated by the tissue inhibitor of metalloproteinase 3 (TIMP3). The aim of the present study was to investigate in an in vitro model of PMNL transepithelial migration and in the intestinal mucosa of patients with CD the expression and regulation of ADAM17 and TIMP3 in intestinal epithelial cells (IEC). ADAM17 and TIMP3 expression was analyzed by Western blotting, RT-PCR, confocal microscopy, and immunohistochemistry by using the T84 model and digestive biopsies. ADAM17 expression in IEC was increased at a posttranscriptional level during the early phase (from 2 to 4 h) of PMNL transepithelial migration whereas TIMP3 was only increased 24 h later. TNF- induced an early upregulation of ADAM17 in T84 cells, whereas PMNL adhesion, H₂O₂, or epithelial tight junction opening alone did not affect the amount of ADAM17. Immunohistochemistry of intestinal biopsies revealed that strong expression of ADAM17 was associated with a high activity of CD. In contrast, TIMP3 was very poorly expressed in these biopsies. ADAM17 and TIMP3 profiling did not correlated with the NOD2/CARD15 status. The ADAM17 activity was higher both in the early phase of PMNL transepithelial migration and in active CD. These results showed early posttranscriptional upregulation of ADAM17 in IEC linked to PMNL transepithelial migration and a high activity of CD.

Crohn's disease; intestinal epithelial cell; neutrophil