title: Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice.
abstract: Deep vein thrombosis (DVT) is a major cause of pulmonary thromboembolism, a leading cause of death in individuals with DVT. Several lines of evidence indicate proinflammatory cytokines such as TNF-α are involved in thrombus formation and resolution, but the roles of IFN-γ remain unclear. To address this issue, we performed ligation of the inferior vena cava to induce DVT in WT and IFN-γ-deficient (Ifng-/-) mice. In WT mice, intrathrombotic IFN-γ levels were elevated progressively as the postligation interval was extended. Thrombus size was substantially smaller at 10 and 14 days in Ifng-/- mice than in WT mice. Intrathrombotic collagen content was remarkably reduced at more than 10 days after the ligation in Ifng-/- mice compared with WT mice. The expression and activity of MMP-9, but not MMP-2, was higher at the late phase in Ifng-/- mice than in WT mice. Moreover, intrathrombotic recanalization was increased in Ifng-/- mice, with enhanced Vegf gene expression, compared with that in WT mice. Activation of the IFN-γ/Stat1 signal pathway suppressed PMA-induced Mmp9 and Vegf gene expression in peritoneal macrophages. Furthermore, administration of anti-IFN-γ mAbs accelerated thrombus resolution in WT mice. Collectively, these findings indicate that IFN-γ can have detrimental roles in thrombus resolution and may be a good molecular target for the acceleration of thrombus resolution in individuals with DVT.
authors.affiliation: Department of Forensic Medicine, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan.
authors.forename: Mizuho
authors.initials: M
authors.lastname: Nosaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishida
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kimura
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kuninaka
authors.forename: Masanori
authors.initials: M
authors.lastname: Inui
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kondo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000378:metabolism; D015870:Gene Expression; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D014682:Vena Cava, Inferior / Q000601:surgery
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D050794:STAT1 Transcription Factor; D042442:Vascular Endothelial Growth Factors; D007371:Interferon-gamma; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate