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

Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1332-43. doi: 10.1152/ajpgi.90641.2008. Epub 2009 Mar 19.


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-alpha. Conversion of inactive TNF-alpha into an active form requires the cleavage of a transmembrane TNF-alpha precursor by the TNF-alpha-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-alpha induced an early upregulation of ADAM17 in T84 cells, whereas PMNL adhesion, H(2)O(2), 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Biopsy
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Colitis / diagnosis
  • Colitis / pathology
  • Colon / metabolism
  • Colon / pathology
  • Crohn Disease / metabolism*
  • Crohn Disease / pathology
  • Epithelial Cells / metabolism
  • Gene Expression / drug effects
  • Gene Expression / physiology
  • Gene Expression Regulation / physiology*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Ileum / metabolism
  • Ileum / pathology
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophils / cytology
  • Neutrophils / pathology
  • Nod2 Signaling Adaptor Protein / genetics
  • Tight Junctions / metabolism
  • Tissue Inhibitor of Metalloproteinase-3 / metabolism*
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antibodies, Monoclonal
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • TIMP3 protein, human
  • Tissue Inhibitor of Metalloproteinase-3
  • Tumor Necrosis Factor-alpha
  • N-Formylmethionine Leucyl-Phenylalanine
  • Hydrogen Peroxide
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human