title: IFN-gamma/JAK/STAT pathway-induced inhibition of DR4 and DR5 expression on endothelial cells is cancelled by cycloheximide-sensitive mechanism: novel finding of cycloheximide-regulating death receptor expression.
abstract: The pathway of interferon gamma (IFN-gamma-induced suppression in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated endothelial cell apoptosis was investigated. rTRAIL triggered apoptosis of human umbilical vein endothelial cells (HUVECs) in a type II cell death manner. IFN-gamma pretreatment significantly suppressed the expression of death receptor 4 (DR4) and DR5 on HUVECs, and inhibited apoptosis in response to TRAIL. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1) and STAT6 but did not enhance phosphorylation of STAT3, Akt and extracellular signal-regulated kinase (ERK) and nuclear translocation of NF-kappaB p65. Janus kinase (JAK)-induced phosphorylation of STAT1/6 appeared to be crucial since chemical inhibition of JAK abolished phosphorylation of STAT1/6, down-regulation of DR4/DR5 expression and IFN-gamma-induced inhibition of TRAIL-mediated apoptosis. IFN-gamma/JAK/STAT-induced suppression was regulated by cycloheximide (CHX)-sensitive mechanism since the use of CHX mimicked the action of chemical inhibition of JAK in regard to DR4/DR5 expression as well as TRAIL-mediated endothelial cell apoptosis. We have not yet clarified precise mechanism, however, the present data provide a novel finding that IFN-gamma/JAK/STAT pathway elicits inhibition of TRAIL-mediated endothelial cell apoptosis through CHX-sensitive suppression of DR4/DR5.
authors.affiliation: First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tanaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
authors.forename: Mami
authors.initials: M
authors.lastname: Tamai
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Nozomi
authors.initials: N
authors.lastname: Iwanaga
authors.forename: Yasumori
authors.initials: Y
authors.lastname: Izumi
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Arima
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Aratake
authors.forename: Mingguo
authors.initials: M
authors.lastname: Huang
authors.forename: Makoto
authors.initials: M
authors.lastname: Kamachi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ida
authors.forename: Tomoki
authors.initials: T
authors.lastname: Origuchi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand; D015534:Trans-Activators / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003513:Cycloheximide