Interleukin-6 involvement in brain arteriovenous malformations.
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-1beta, tumor necrosis factor-alpha, 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.
Chen
Yongmei
Y
Center for Cerebrovascular Research, University of California at San Francisco, 1001 Potrero Avenue, San Francisco, CA, USA.
Pawlikowska
Ludmila
L
Yao
Jianhua S
JS
Shen
Fanxia
F
Zhai
Wenwu
W
Achrol
Achal S
AS
Lawton
Michael T
MT
Kwok
Pui-Yan
PY
Yang
Guo-Yuan
GY
Young
William L
WL
D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013223:Statistics as Topic
D015850:Interleukin-6; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases