Cardiotrophin-1 stimulates intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human aortic endothelial cells.
Intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play critical roles in mediating monocyte adhesion to the vascular endothelium and monocyte migration into the subendothelial regions of the vessels. Inasmuch as cardiotrophin-1 (CT-1), an IL-6-type cytokine, was expressed in human atherosclerotic plaque, we examined whether CT-1 induces monocyte adhesion and migration by stimulating gene and protein expressions of ICAM-1 and MCP-1 in human aortic endothelial cells (HAECs). Immunocytochemistry revealed that CT-1 increased intensity of ICAM-1 and MCP-1 immunoreactivity in HAECs. Adhesion assay and chemotaxis assay revealed that CT-1 increased human monocytic THP-1 cell adhesion to HAECs and promoted chemotaxis in THP-1 cells, which were attenuated by anti-ICAM-1 and anti-MCP-1 antibody, respectively. Western blot analysis showed that CT-1 increased phosphorylation of ERK1/2 MAP kinase, p38 MAP kinase, and Akt and that their inhibitors, PD-98059, SB-203580, and LY-294002, respectively, inhibited phosphorylation. RNase protection assay and ELISA demonstrated that CT-1 increased gene and protein expressions of ICAM-1 and MCP-1. EMSA revealed that CT-1 enhanced NF-kappaB DNA-binding activity. CT-1-mediated upregulation of ICAM-1 and MCP-1 was suppressed by PD-98059, SB-203580, LY-294002, and parthenolide. The present study demonstrates that CT-1 promotes monocyte adhesion and migration by stimulating ICAM-1 and MCP-1 through mechanisms that involve ERK1/2 MAP kinase, p38 MAP kinase, phosphatidylinositol 3-kinase, and NF-kappaB pathways and suggests that CT-1 plays an important role in the pathophysiology of vascular inflammation and atherosclerosis.
Institute for Clinical Research, National Hospital Organization Kagoshima Medical Center, 8-1 Shiroyama-cho, Kagoshima 892-0853, Japan.
Tomoko
T
Ichiki
Michihisa
M
Jougasaki
Manabu
M
Setoguchi
Junichi
J
Imamura
Hitoshi
H
Nakashima
Tatsuru
T
Matsuoka
Masahiro
M
Sonoda
Kazuhiko
K
Nakamura
Shinichi
S
Minagoe
Chuwa
C
Tei
D000368:Aged; D050197:Atherosclerosis / Q000473:pathology; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D002633:Chemotaxis / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis; D016207:Cytokines / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000096:biosynthesis; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D023282:Nuclease Protection Assays; D010766:Phosphorylation; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification
D018932:Chemokine CCL2; D016207:Cytokines; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D050822:Cytokine Receptor gp130; D012313:RNA; C092073:cardiotrophin 1; D020928:Mitogen-Activated Protein Kinases