Interleukin-6 involvement in brain arteriovenous malformations

Authors

  • Yongmei Chen MD, PhD,

    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
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  • Ludmila Pawlikowska PhD,

    1. Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA
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  • Jianhua S. Yao MD, PhD,

    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
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  • Fanxia Shen MD,

    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
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  • Wenwu Zhai MD, PhD,

    1. Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA
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  • Achal S. Achrol BS,

    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
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  • Michael T. Lawton MD,

    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Departments of Neurological Surgery, University of California at San Francisco, San Francisco, CA
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  • Pui-Yan Kwok MD, PhD,

    1. Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA
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  • Guo-Yuan Yang MD, PhD,

    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
    3. Departments of Neurological Surgery, University of California at San Francisco, San Francisco, CA
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  • William L. Young MD

    Corresponding author
    1. Center for Cerebrovascular Research, University of California at San Francisco, San Francisco, CA
    2. Department of Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, CA
    3. Departments of Neurological Surgery, University of California at San Francisco, San Francisco, CA
    4. Departments of Neurology, University of California at San Francisco, San Francisco, CA
    • University of California at San Francisco, 1001 Potrero Avenue, Rm 3c-38, San Francisco, CA
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Abstract

We recently reported that the GG genotype of the interleukin-6 (IL-6)–174G>C promoter polymorphism is associated with clinical presentation of intracranial hemorrhage in brain arteriovenous malformation (AVM) patients. In this study, we investigated whether tissue IL-6 expression was associated with IL-6–174G>C genotype, and whether IL-6 was linked to downstream targets involved in angiogenesis and vascular instability. Our results showed that the highest IL-6 protein levels in brain AVM tissue were associated with IL-6–174GG genotype (GG: 57.7 ± 20.2; GC: 35.6 ± 26.6; CC: 13.9 ± 10.2pg/mg; p = 0.001). IL-6 protein levels were increased in AVM tissue from patients with hemorrhagic presentation compared with patients without hemorrhage (55 ± 22 vs 40 ± 27pg/mg; p = 0.038). IL-6 messenger RNA expression strongly correlated with messenger RNA levels of IL-1β, tumor necrosis factor-α, IL-8, matrix metalloproteinase-3 (MMP-3), MMP-9, and MMP-12. We further investigated the plausibility of IL-6 being an upstream cytokine responsible for initiating the angiogenic cascade by cell culture and animal experiments. IL-6 induced MMP-3 and MMP-9 expression and activity in mouse brain and increased proliferation and migration of cerebral endothelial cells. Together, our results suggest that the IL-6 genotype associated with intracranial hemorrhage modulates IL-6 expression in brain AVM tissue, which is consistent with the hypothesis that inflammatory processes induce angiogenic activity possibly contributory to brain AVM intracranial hemorrhage. Ann Neurol 2005

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