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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 1

Intrathrombotic IFN-γ expression in WT mice after IVC ligation.

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Intrathrombotic IFN-γ expression in WT mice after IVC ligation.
(A) Ifnγ...
(A) Ifnγ gene expression was examined by real-time RT-PCR as described in Methods. All values represent mean ± SEM (n = 6). **P < 0.01, versus day 3; ##P < 0.01, versus day 10. (B) Intrathrombotic IFN-γ protein contents were determined at the indicated time intervals after IVC ligation as described in Methods. All values represent mean ± SEM (n = 6). **P < 0.01, versus day 5; *P < 0.05, versus day 5; #P < 0.05, versus day 10. (C) A double-color immunofluorescence analysis of IFN-γ–expressing cells in the thrombus. The samples were immunostained with the combination of anti-F4/80 mAbs and anti–IFN-γ pAbs as described in Methods. The fluorescent images were digitally merged in the right panel. Representative results from 6 independent experiments are shown here. Original magnification, ×400. Blue, nuclear staining by DAPI.
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