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Absence of IFN-γ accelerates thrombus resolution through enhanced MMP-9 and VEGF expression in mice
Mizuho Nosaka, … , Naofumi Mukaida, Toshikazu Kondo
Mizuho Nosaka, … , Naofumi Mukaida, Toshikazu Kondo
Published June 6, 2011
Citation Information: J Clin Invest. 2011;121(7):2911-2920. https://doi.org/10.1172/JCI40782.
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Research Article Hematology

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

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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.

Authors

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

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Figure 10

The effects of anti–IFN-γ mAb administration on thrombus resolution.

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The effects of anti–IFN-γ mAb administration on thrombus resolution.
WT ...
WT mice were i.p. administered anti–IFN-γ mAbs or isotype-matched IgG as described in Methods. At 14 days after the IVC ligation, thrombus weight (A) and intrathrombotic collagen contents (B), thrombosed blood flow (C), and the gene expression of MMP-9 (D) and VEGF (E) were measured and shown here. All values represent the mean ± SEM (n = 6 animals). *P < 0.05; **P < 0.01, anti–IFN-γ mAbs versus control IgG.
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