title: Interferon-Gamma Increases Endothelial Permeability by Causing Activation of p38 MAP Kinase and Actin Cytoskeleton Alteration.
abstract: Interferon-gamma (IFN-γ) is known to potentiate the progression of inflammatory diseases, such as inflammatory bowel disease and atherosclerosis. IFN-γ has been found to disrupt the barrier integrity of epithelial and endothelial cell both in vivo and in vitro. However, the mechanisms of IFN-γ underlying increased endothelial cell permeability have not been extensively elucidated. We reported that IFN-γ exhibits a biphasic nature in increasing endothelial permeability. The changes observed in the first phase (4-8 h) involve cell retraction and rounding in addition to condensed peripheral F-actin without a significant change in the F-/G-actin ratio. However, cell elongation, stress fiber formation, and an increased F-/G-actin ratio were noticed in the second phase (16-24 h). Consistent with our finding from the permeability assay, IFN-γ induced the formation of intercellular gaps in both phases. A delayed phase of increased permeability was observed at 12 h, which paralleled the onset of cell elongation, stress fiber formation, and increased F-/G-actin ratio. In addition, IFN-γ stimulated p38 mitogen-activated protein (MAP) kinase phosphorylation over a 24 h period. Inhibition of p38 MAP kinase by SB203580 prevented increases in paracellular permeability, actin rearrangement, and increases in the F-/G-actin ratio caused by IFN-γ. Our results suggest that p38 MAP kinase is activated in response to IFN-γ and causes actin rearrangement and altered cell morphology, which in turn mediates endothelial cell hyperpermeability. The F-/G-actin ratio might be involved in the regulation of actin distribution and cell morphology rather than the increased permeability induced by IFN-γ.
authors.affiliation: 1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Chin Theng
authors.initials: CT
authors.lastname: Ng
authors.affiliation: 1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Lai Yen
authors.initials: LY
authors.lastname: Fong
authors.affiliation: 1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Mohd Roslan
authors.initials: MR
authors.lastname: Sulaiman
authors.affiliation: 2 Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Mohamad Aris Mohd
authors.initials: MA
authors.lastname: Moklas
authors.affiliation: 2 Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Yoke Keong
authors.initials: YK
authors.lastname: Yong
authors.affiliation: 1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Muhammad Nazrul
authors.initials: MN
authors.lastname: Hakim
authors.affiliation: 1 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia , UPM Serdang, Selangor, Malaysia .
authors.forename: Zuraini
authors.initials: Z
authors.lastname: Ahmad
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D007093:Imidazoles; D007371:Interferon-gamma / Q000494:pharmacology*; D010766:Phosphorylation; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D007093:Imidazoles; D011725:Pyridines; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580