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Interleukin-6 involvement in brain arteriovenous malformations.
Yongmei Chen1, Ludmila Pawlikowska, Jianhua S Yao
1Center for Cerebrovascular Research, University of California at San Francisco, 1001 Potrero Avenue, San Francisco, CA, USA.
Annals of Neurology
|November 10, 2005
Summary
The interleukin-6 (IL-6) GG genotype is linked to higher IL-6 levels in brain arteriovenous malformation (AVM) tissue, increasing hemorrhage risk. This suggests inflammation drives AVM angiogenesis and bleeding.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Brain arteriovenous malformations (AVMs) are prone to intracranial hemorrhage.
- The interleukin-6 (IL-6) -174G>C promoter polymorphism has been linked to AVM hemorrhage risk.
- The relationship between IL-6 genotype, IL-6 expression, and AVM pathogenesis remains unclear.
Purpose of the Study:
- To investigate the association between IL-6 genotype and IL-6 expression in brain AVM tissue.
- To explore the link between IL-6 and downstream targets involved in angiogenesis and vascular instability.
- To determine if IL-6 plays a role in the angiogenic cascade contributing to AVM hemorrhage.
Main Methods:
- Genotyping of the IL-6 -174G>C promoter polymorphism in AVM patients.
- Quantification of IL-6 protein and messenger RNA (mRNA) levels in AVM tissue.
- Correlation analysis between IL-6 levels, genotype, and clinical presentation (hemorrhage).
- In vitro cell culture and in vivo animal experiments to assess IL-6's effect on angiogenesis-related factors.
Main Results:
- The IL-6 -174GG genotype was associated with significantly higher IL-6 protein levels in AVM tissue compared to GC and CC genotypes (p=0.001).
- IL-6 protein levels were elevated in AVM tissue from patients with a history of hemorrhage (p=0.038).
- IL-6 mRNA expression strongly correlated with mRNA levels of inflammatory cytokines (IL-1beta, TNF-alpha, IL-8) and matrix metalloproteinases (MMP-3, MMP-9, MMP-12).
- IL-6 induced MMP-3 and MMP-9 expression and activity, and enhanced cerebral endothelial cell proliferation and migration in experimental models.
Conclusions:
- The IL-6 genotype influences IL-6 expression within brain AVM tissue.
- Elevated IL-6 expression in AVMs, particularly in those with hemorrhage, suggests a role for inflammation in disease progression.
- IL-6 promotes angiogenic processes through MMP induction and endothelial cell activation, potentially contributing to AVM vascular instability and hemorrhage.