Background: Tumor necrosis factor α (TNF-α) plays a major role in the tissue-damaging immune response in inflammatory bowel diseases (IBDs). The tissue concentration of TNF-α is related to the activity of “A Disintegrin And Metalloprotease” (ADAMs), enzymes that process membrane-bound TNF-α and liberate the TNF-α trimer into the extracellular environment. Although IBD-related inflammation is associated with high ADAM17 levels, the contribution of other members of the ADAMs family is not known. In this study, we characterized the expression of other TNF-α convertases (i.e., ADAM9, ADAM10, and ADAM19) in IBD.
Methods: Normal and IBD biopsies were examined for the content of ADAMs by real-time polymerase chain reaction, Western blotting and immunohistochemistry. ADAM19 was also analyzed in intestinal epithelial cells and normal colonic explants stimulated with inflammatory cytokines and in ex vivo biopsies taken from IBD patients before and after a successful infliximab treatment.
Results: ADAM19 RNA transcripts and protein were upregulated in patients with ulcerative colitis and, to a lesser extent, in patients with Crohn's disease compared with normal controls. In contrast, ADAM9 and ADAM10 expression did not differ between patients with IBD and controls. Immunohistochemical analysis showed that epithelial cells were the major source of ADAM19 in IBD. ADAM19 expression was increased in colonic epithelial cell lines and normal colonic explants by TNF-α, interleukin 21 and interleukin 6, and was downregulated in IBD tissue by infliximab.
Conclusions: These findings suggest the existence of a positive feedback mechanism involving cytokines and ADAM19 that can amplify cytokine production in IBD.
Article first published online 6 February 2013
*Department of Internal Medicine, University of Rome “Tor Vergata”, Rome, Italy
†Unit of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
‡Institute of Cell and Molecular Science Centre for Infectious Diseases, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Reprints: Giovanni Monteleone, MD, PhD, Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy (e-mail: email@example.com).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).
Supported by “Fondazione Umberto Di Mario ONLUS” (Rome, Italy), Giuliani S.p.a. (Milan, Italy), funding for the IPODD consortium under Grant Agreement 202020 of the Seventh Research Framework Programme of the European Union.
The authors have no conflicts of interest to disclose.
Received May 31, 2012
Accepted June 29, 2012