title: Induction of endothelial-leukocyte interaction by interferon-gamma requires coactivation of nuclear factor-kappaB.
abstract: To determine whether nuclear factor (NF)-kappaB is necessary to confer endothelial cell responsiveness to interferon (INF)-gamma in terms of vascular cell adhesion molecule (VCAM)-1 expression and leukocyte adhesion, human endothelial cells were treated with IFN-gamma in the presence of low concentrations (LCs) of interleukin (IL)-1alpha (</=100 pg/mL), which activates NF-kappaB but does not induce VCAM-1 expression. Although IFN-gamma induced major histocompatibility complex class II antigen expression and although a high concentration of IL-1alpha (10 ng/mL) induced leukocyte adhesion and VCAM-1 expression, neither IFN-gamma nor LC IL-1alpha was able to induce VCAM-1 expression or leukocyte adhesion. However, the combination of IFN-gamma and LC IL-1alpha induced VCAM-1 expression and increased leukocyte adhesion (67% and 49% of high-concentration IL-1alpha, respectively). Electrophoretic mobility shift assays and immunoblotting of nuclear extracts showed that IFN-gamma activated signal transducers and activators of transcription (STAT)-1alpha and interferon regulatory factor (IRF)-1 but not NF-kappaB, whereas LC IL-1alpha activated NF-kappaB but not STAT-1alpha or IRF-1. Nuclear run-on studies showed that LC IL-1alpha is necessary but not sufficient for inducing VCAM-1 gene transcription and that the combination of IFN-gamma and LC IL-1alpha is required for full VCAM-1 gene transcription. These findings suggest that factors that activate NF-kappaB can synergize with IFN-gamma in promoting endothelial-leukocyte interaction.
authors.affiliation: Vascular Medicine Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: R
authors.initials: R
authors.lastname: De Caterina
authors.forename: T
authors.initials: T
authors.lastname: Bourcier
authors.forename: U
authors.initials: U
authors.lastname: Laufs
authors.forename: V
authors.initials: V
authors.lastname: La Fata
authors.forename: G
authors.initials: G
authors.lastname: Lazzerini
authors.forename: A S
authors.initials: AS
authors.lastname: Neish
authors.forename: P
authors.initials: P
authors.lastname: Libby
authors.forename: J K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D050835:Interferon Regulatory Factors; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D007375:Interleukin-1; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology; D000099218:Interferon Regulatory Factor-4
chemical_list: D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma; D007375:Interleukin-1; D016328:NF-kappa B; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D000099218:Interferon Regulatory Factor-4; C079868:gamma interferon activation factor