title: Mechanism of interferon-gamma-induced increase in T84 intestinal epithelial tight junction.
abstract: Interferon-gamma (IFN-gamma) is an important proinflammatory cytokine that plays a central role in the intestinal inflammatory process of inflammatory bowel disease. IFN-gamma induced disturbance of the intestinal epithelial tight junction (TJ) barrier has been postulated to be an important mechanism contributing to intestinal inflammation. The intracellular mechanisms that mediate the IFN-gamma induced increase in intestinal TJ permeability remain unclear. The aim of this study was to examine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in the regulation of the IFN-gamma induced increase in intestinal TJ permeability using the T84 intestinal epithelial cell line. IFN-gamma caused an increase in T84 intestinal epithelial TJ permeability and depletion of TJ protein, occludin. The IFN-gamma induced increase in TJ permeability and alteration in occludin protein was associated with rapid activation of PI3-K; and inhibition of PI3-K activation prevented the IFN-gamma induced effects. IFN-gamma also caused a delayed but more prolonged activation of nuclear factor-kappaB (NF-kappaB); inhibition of NF-kappaB also prevented the increase in T84 TJ permeability and alteration in occludin expression. The IFN-gamma induced activation of NF-kappaB was mediated by a cross-talk with PI3-K pathway. In conclusion, the IFN-gamma induced increase in T84 TJ permeability and alteration in occludin protein expression were mediated by the PI3-K pathway. These results show for the first time that the IFN-gamma modulation of TJ protein and TJ barrier function is regulated by a cross-talk between PI3-K and NF-kappaB pathways.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-5271, USA.
authors.forename: Michel A
authors.initials: MA
authors.lastname: Boivin
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Roy
authors.forename: Angela
authors.initials: A
authors.lastname: Bradley
authors.forename: John C
authors.initials: JC
authors.lastname: Kennedy
authors.forename: Tuhama
authors.initials: T
authors.lastname: Rihani
authors.forename: Thomas Y
authors.initials: TY
authors.lastname: Ma
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D062793:Occludin; D010539:Permeability / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; D008565:Membrane Proteins; D016328:NF-kappa B; C568985:OCLN protein, human; D062793:Occludin; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases