Interferon-γ activates transglutaminase 2 via a phosphatidylinositol-3-kinase-dependent pathway: implications for celiac sprue therapy.
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.
Department of Chemical Engineering, Stanford University, 380 Roth Way, Stanford, CA 94305, USA.
Thomas R
TR
Diraimondo
Cornelius
C
Klöck
Chaitan
C
Khosla
D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D002460:Cell Line; D020895:Enterocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology* / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction / Q000502:physiology; D011503:Transglutaminases / Q000378:metabolism*
D007371:Interferon-gamma; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D058539:Phosphatidylinositol 3-Kinase; D019204:GTP-Binding Proteins