Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice

Mizuho Nosaka, Yuko Ishida, Akihiko Kimura, Yumi Kuninaka, Masanori Inui, Naofumi Mukaida, Toshikazu Kondo

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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.

Original languageEnglish
Pages (from-to)2911-2920
Number of pages10
JournalJournal of Clinical Investigation
Volume121
Issue number7
DOIs
Publication statusPublished - 2011 Jul 1

ASJC Scopus subject areas

  • Medicine(all)

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    Nosaka, M., Ishida, Y., Kimura, A., Kuninaka, Y., Inui, M., Mukaida, N., & Kondo, T. (2011). Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice. Journal of Clinical Investigation, 121(7), 2911-2920. https://doi.org/10.1172/JCI40782