TY - JOUR
T1 - High expression of the "A disintegrin and metalloprotease" 19 (ADAM19), a sheddase for TNF-a in the mucosa of patients with inflammatory bowel diseases
AU - Franzè, Eleonora
AU - Caruso, Roberta
AU - Stolfi, Carmine
AU - Sarra, Massimiliano
AU - Cupi, Maria Laura
AU - Ascolani, Marta
AU - Sedda, Silvia
AU - Antenucci, Claudia
AU - Ruffa, Alessandra
AU - Caprioli, Flavio
AU - MacDonald, Thomas T.
AU - Pallone, Francesco
AU - Monteleone, Giovanni
PY - 2013/3
Y1 - 2013/3
N2 - Background: Tumor necrosis factor a (TNF-a) plays a major role in the tissue-damaging immune response in inflammatory bowel diseases (IBDs). The tissue concentration of TNF-a is related to the activity of "A Disintegrin And Metalloprotease" (ADAMs), enzymes that process membranebound TNF-a and liberate the TNF-a 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-a 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-a, 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.
AB - Background: Tumor necrosis factor a (TNF-a) plays a major role in the tissue-damaging immune response in inflammatory bowel diseases (IBDs). The tissue concentration of TNF-a is related to the activity of "A Disintegrin And Metalloprotease" (ADAMs), enzymes that process membranebound TNF-a and liberate the TNF-a 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-a 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-a, 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.
KW - ADAM19
KW - Colitis
KW - Inflammatory bowel disease
KW - TNF-a
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UR - http://www.scopus.com/inward/citedby.url?scp=84876368553&partnerID=8YFLogxK
U2 - 10.1097/MIB.0b013e31828028e8
DO - 10.1097/MIB.0b013e31828028e8
M3 - Article
C2 - 23429442
AN - SCOPUS:84876368553
VL - 19
SP - 501
EP - 511
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
SN - 1078-0998
IS - 3
ER -