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TNF-alpha neutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis.

Abstract
Tumor necrosis factor alpha (TNF-alpha) is an important mediator of programmed cell death, and TNF-alpha blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-alpha therapy in CD remains poorly understood. SAMP1/YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-alpha therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-alpha antibodies in human CD, a single injection of a chimeric anti-murine TNF-alpha antibody into SAMP1/YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-alpha-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-alpha reduced membrane bound FAS/CD95 expression in IEC from SAMP1/YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-alpha therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.
AuthorsMarco Marini, Giorgos Bamias, Jesús Rivera-Nieves, Christopher A Moskaluk, Sharon B Hoang, William G Ross, Theresa T Pizarro, Fabio Cominelli
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 14 Pg. 8366-71 (Jul 08 2003) ISSN: 0027-8424 [Print] United States
PMID12832622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibodies, Monoclonal
  • Recombinant Fusion Proteins
  • Tumor Necrosis Factor-alpha
Topics
  • Animals
  • Antibodies, Monoclonal (immunology, pharmacology)
  • Apoptosis (drug effects)
  • Crohn Disease
  • Disease Models, Animal
  • Epithelial Cells (drug effects, pathology)
  • Ileitis (drug therapy, genetics, pathology)
  • In Situ Nick-End Labeling
  • Intestinal Mucosa (drug effects, pathology)
  • Leukocytes, Mononuclear (pathology)
  • Mice
  • Mice, Inbred Strains
  • Recombinant Fusion Proteins (immunology, pharmacology)
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology)

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