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Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy.

Abstract
The mechanism for activation of extracellular transglutaminase 2 (TG2) in the small intestine remains a fundamental mystery in our understanding of celiac sprue pathogenesis. Using the T84 human enterocytic cell line, we show that interferon-γ (IFN-γ), the predominant cytokine secreted by gluten-reactive T cells in the celiac intestine, activates extracellular TG2 in a dose-dependent manner. IFN-γ mediated activation of TG2 requires phosphatidylinositol-3-kinase (PI3K) activity, but is uninfluenced by a number of other kinases reported to be active in T84 cells. Pharmacological inhibition of PI3K in the presence of IFN-γ prevents TG2 activation as well as the previously characterized increase in transepithelial permeability. Our findings therefore establish PI3K as an attractive target for celiac sprue therapy, a possibility that is underscored by the encouraging safety profiles of several PI3K inhibitors undergoing human clinical trials.
AuthorsThomas R Diraimondo, Cornelius Klöck, Chaitan Khosla
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 341 Issue 1 Pg. 104-14 (Apr 2012) ISSN: 1521-0103 [Electronic] United States
PMID22228808 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Interferon-gamma
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • Phosphatidylinositol 3-Kinase
  • GTP-Binding Proteins
Topics
  • Amino Acid Sequence
  • Celiac Disease (drug therapy, enzymology, etiology)
  • Cell Line
  • Enterocytes (drug effects, enzymology, physiology)
  • Enzyme Activation (physiology)
  • GTP-Binding Proteins (metabolism)
  • Humans
  • Interferon-gamma (pharmacology, therapeutic use)
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinase (metabolism)
  • Protein Glutamine gamma Glutamyltransferase 2
  • Signal Transduction (physiology)
  • Transglutaminases (metabolism)

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