Interleukin-6 upregulates expression of KDR and stimulates proliferation of human cerebrovascular smooth muscle cells.
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.
Yao
Jianhua S
JS
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94110, USA.
Zhai
Wenwu
W
Fan
Yongfeng
Y
Lawton
Michael T
MT
Barbaro
Nicholas M
NM
Young
William L
WL
Yang
Guo-Yuan
GY
D000328:Adult; D000368:Aged; D001165:Arteriovenous Malformations / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D015850:Interleukin-6; D012333:RNA, Messenger; D040301:Vascular Endothelial Growth Factor Receptor-2; D020780:Matrix Metalloproteinase 9