Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells

J Cereb Blood Flow Metab. 2007 Mar;27(3):510-20. doi: 10.1038/sj.jcbfm.9600365. Epub 2006 Jul 5.


Interleukin-6 (IL-6) may play multiple roles in angiogenesis and vascular remodeling. Our previous study showed that a promoter polymorphism (174G>C) in IL-6 is associated with brain arteriovenous malformation hemorrhage; tissue expression is related to genotype. In this study, we investigated the effects of IL-6 on human cerebral smooth muscle cells (HCSMCs) and smooth muscle cells isolated from brain arteriovenous malformation surgical specimens (AVM SMCs) and surgical controls (control HCSMCs--from structurally normal temporal lobe taken during surgical treatment of epilepsy patients). We found that IL-6 (1.1+/-0.27 versus 0.37+/-0.04 pg/mL, n=5, P<0.05) and endogenous vascular endothelial growth factor (VEGF) receptor II (kinase domain-containing receptor (KDR), 15+/-3 versus 1.5+/-3 pg/mL, n=5, P<0.05) were increased in brain AVM SMCs compared with control HCSMCs. Further research revealed that IL-6 could stimulate SMC proliferation, VEGF release, and KDR activation in control HCSMCs. It could also stimulate KDR phosphorylation in control HCSMCs, further confirming a unique role of IL-6 in the triggering of KDR. Interleukin-6 could increase matrix metalloproteinase-9 (MMP-9) secretion through activating KDR in control HCSMCs (P<0.05 versus control). Inhibiting IL-6-induced KDR could reduce MMP-9 activity at least 50% compared with the control group (P<0.05). Increased MMP-9 activity was accompanied by increased control HCSMC proliferation, and blocking MMP-9 activity significantly reduced IL-6-induced control HCSMC proliferation (P<0.05). Collectively, our results show that IL-6 could activate, amplify, and maintain the angiogenic cascade in HCSMCs. A novel role of IL-6 during HCSMC proliferation is upregulating KDR expression and phosphorylation. The results may contribute to the angiogenic phenotype of human brain vascular diseases, such as brain AVM.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Arteriovenous Malformations / metabolism
  • Blotting, Western
  • Brain / blood supply
  • Brain / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Cerebrovascular Circulation
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunohistochemistry
  • Infant
  • Interleukin-6 / metabolism*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / metabolism*
  • Phosphorylation
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*


  • Interleukin-6
  • RNA, Messenger
  • Vascular Endothelial Growth Factor Receptor-2
  • Matrix Metalloproteinase 9