Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro.
Circulating blood endothelial progenitor cells (EPCs) contribute to postnatal vasculogenesis, providing a novel therapeutic target for vascular diseases. However, the molecular mechanism of EPC-induced vasculogenesis is unknown. Interleukin-6 plays multiple functions in angiogenesis and vascular remodeling. Our previous study demonstrated that the polymorphism (174G>C) in IL-6 gene promoter was associated with brain vascular disease. In this study, we investigated if IL-6 receptor is expressed in human EPCs derived from circulating mononuclear cells, and if interleukin-6 (IL-6) stimulates EPC angiogenesis in vitro. First, we isolated and cultured mononuclear cells from adult human circulating blood. We obtained EPC clones that were further cultured and expended for the angiogenesis study. We found that the EPCs possessed human mature endothelial cell phenotypes; however, they proliferated much faster than mature endothelial cells (P<0.05). We then found that IL-6 receptor (gp-80) was expressed in the EPCs, and that administration of IL-6 could activate receptor gp80/gp130 signaling pathways including downstream extracellular signal-regulated kinase 1/2 and STAT3 phosphorylation in EPCs. Furthermore, IL-6 stimulated EPC proliferation, migration, and matrigel tube formation in a dose-dependent manner (P<0.05); anti-IL-6 antibodies or IL-6 receptor could abolish these effects (P<0.05). These results suggest that IL-6 plays a crucial role in the biologic behavior of blood-derived EPCs, which may help clarify the mechanism of IL-6 inflammatory-related diseases.
Fan
Yongfeng
Y
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA 94110, USA.
Ye
Jianqin
J
Shen
Fanxia
F
Zhu
Yiqian
Y
Yeghiazarians
Yerem
Y
Zhu
Wei
W
Chen
Yongmei
Y
Lawton
Michael T
MT
Young
William L
WL
Yang
Guo-Yuan
GY
D000328:Adult; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000819:agonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D019947:Receptors, Interleukin-6 / Q000819:agonists / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
C508600:IL6 protein, human; C508603:IL6R protein, human; C494199:IL6ST protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3