Interferon-γ induces biphasic changes in caldesmon localization as well as adherens junction organization and expression in HUVECs. (November 2018)

• Record Type: Journal Article
• Authors: Ng, Chin Theng; Fong, Lai Yen; Yong, Yoke Keong; Hakim, Muhammad Nazrul; Ahmad, Zuraini
• Is Part Of: Cytokine. Volume 111(2018)
• Page Start: 541
• Page End: 550
• Publication Date: 2018-11
• Subjects: Interferon-gamma -- Human umbilical vein endothelial cells -- Caldesmon -- Adherens junction -- p38 MAP kinase -- Proinflammatory cytokines; IFN-γ Interferon-gamma -- AJs adherens junctions -- VE-cadherin vascular endothelial-cadherin -- MAP mitogen-activated protein; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2018.06.010
• Languages: English
• ISSNs: 1043-4666

Abstract

Highlights: IFN-γ induces biphasic changes in caldesmon structure, AJ organization and expression. IFN-γ induces caldesmon redistribution from the cell periphery to the cytoplasm. IFN-γ induces AJ redistribution, decreases AJ junctional areas and protein expression. IFN-γ affects caldesmon-actin and caldemon-myosin complexes. p38 MAP kinase is not a key regulator that governs the IFN-γ-induced cellular changes. Abstract: Endothelial barrier dysfunction leads to increased endothelial permeability and is an early step in the development of vascular inflammatory diseases such as atherosclerosis. Interferon-γ (IFN-γ), a proinflammatory cytokine, is known to cause increased endothelial permeability. However, the mechanisms by which IFN-γ disrupts the endothelial barrier have not been clarified. This study aimed to investigate how IFN-γ impairs the endothelial barrier integrity by specifically examining the roles of caldesmon, adherens junctions (AJs) and p38 mitogen-activated protein (MAP) kinase in IFN-γ-induced endothelial barrier dysfunction. IFN-γ exhibited a biphasic effect on caldesmon localization and both the structural organization and protein expression of AJs. In the early phase (4-8 h), IFN-γ induced the formation of peripheral caldesmon bands and discontinuous AJs, while AJ protein expression was unchanged. Interestingly, IFN-γ also stimulated caldesmon phosphorylation, resulting in actin dissociation from caldesmon at 8 h. Conversely, changes seen in the late phase (16–24 h) included cytoplasmic caldesmon dispersal, AJ linearization and junctional area reduction, which were associated with reduced membrane, cytoskeletal and total AJ protein expression. In addition, IFN-γ enhanced myosin binding to caldesmon at 12 h and persisted up to 24 h. Furthermore, inhibition of p38 MAP kinase by SB203580 did not reverse either the early or late phase changes observed. These data suggest that IFN-γ may activate signaling molecules other than p38 MAP kinase. In conclusion, our findings enhance the current understanding of how IFN-γ disrupts endothelial barrier function and reveal potential therapeutic targets, such as caldesmon and AJs, for the treatment of IFN-γ-associated vascular inflammatory diseases.