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.
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Authors | Thomas R Diraimondo, Cornelius Klöck, Chaitan Khosla |
Journal | The 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 |
PMID | 22228808
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Interferon-gamma
- Protein Glutamine gamma Glutamyltransferase 2
- Transglutaminases
- Phosphatidylinositol 3-Kinase
- GTP-Binding Proteins
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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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