Intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP)-1 play critical roles in mediating monocyte adhesion to the vascular endothelium and monocyte migration into the subendothelial regions of the vessels. As cardiotrophin (CT)-1, one of the interleukin-6-type cytokines, was expressed in the 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 intensities of ICAM-1 and MCP-1 immunoreactivities 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, each of which was attenuated by anti-ICAM-1 antibody and anti-MCP-1 antibody, respectively. Western blot analysis showed that CT-1 increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase, p38 MAP kinase, and Akt, and that their respective inhibitor, PD98059, SB203580, and LY294002 inhibited each phosphorylation. Ribonuclease protection assay and enzyme-linked immunosorbent assay demonstrated that CT-1 increased gene and protein expressions of ICAM-1 and MCP-1. Electrophrenic mobility shift assay revealed that CT-1 enhanced nuclear factor -kappa B (NF-B) DNA binding activity. CT-1-mediated up-regulation of ICAM-1 and MCP-1 was suppressed by PD98059, SB203580, LY294002, and parthenolide. This study demonstrates that CT-1 promotes monocyte adhesion and migration by stimulating ICAM-1 and MCP-1 through the mechanisms which involve ERK 1/2 MAP kinase, p38 MAP kinase, phosphatidylinositol 3-kinase, and NF-B pathways, and suggests that CT-1 plays an important role in the pathophysiology of vascular inflammation and atherosclerosis.